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Volume 31,Issue 11,2024 Table of Contents
2024, 31(11):1043-1050.
Abstract:
Chimeric antigen receptor gene-modified T-cell (CAR-T cell), represented by the target CD19, has achieved breakthrough progress in the treatment of B-cell malignancies. However, with the increasing number of patients undergoing CAR-T cell therapy, the issue of relapse and resistance has become particularly prominent and is now a major clinical challenge and a research hotspot in the field. In recent years, in addition to immune escape due to antigen loss and treatment insensitivity caused by CAR-T cells dysfunction, progress has been made in understanding resistance mechanisms caused by intrinsic factors of tumor cells. Using high throughput screening system, resistance mechanisms mediated by downregulation or deficient expression of pro-apoptotic molecules (such as NOXA, FADD) and adhesion molecules (such as CD58, ICAM1) have been identified. Several strategies have been developed to reverse these resistance mechanisms, such as HDAC inhibitors combined with CAR-T cell therapy to treat NOXA-low expressing nonHodgkin lymphoma; pretreatment of CAR-T cells with epigenetic drugs to enhance their antitumor efficacy and persistence; using gene editing technologies to relieve gene suppression and enhance CAR-T cell activity; and overexpressing cytokines to improve tumor microenvironment. Some of these strategies have already been clinically validated. This review aims to summarize the existing resistance mechanisms to CAR-T cell therapy and their targeted reversal strategies, analyze the clinical outcomes of related studies, and provide new insights into enhancing CAR-T cell efficacy in B-cell malignancies.
Chimeric antigen receptor gene-modified T-cell (CAR-T cell), represented by the target CD19, has achieved breakthrough progress in the treatment of B-cell malignancies. However, with the increasing number of patients undergoing CAR-T cell therapy, the issue of relapse and resistance has become particularly prominent and is now a major clinical challenge and a research hotspot in the field. In recent years, in addition to immune escape due to antigen loss and treatment insensitivity caused by CAR-T cells dysfunction, progress has been made in understanding resistance mechanisms caused by intrinsic factors of tumor cells. Using high throughput screening system, resistance mechanisms mediated by downregulation or deficient expression of pro-apoptotic molecules (such as NOXA, FADD) and adhesion molecules (such as CD58, ICAM1) have been identified. Several strategies have been developed to reverse these resistance mechanisms, such as HDAC inhibitors combined with CAR-T cell therapy to treat NOXA-low expressing nonHodgkin lymphoma; pretreatment of CAR-T cells with epigenetic drugs to enhance their antitumor efficacy and persistence; using gene editing technologies to relieve gene suppression and enhance CAR-T cell activity; and overexpressing cytokines to improve tumor microenvironment. Some of these strategies have already been clinically validated. This review aims to summarize the existing resistance mechanisms to CAR-T cell therapy and their targeted reversal strategies, analyze the clinical outcomes of related studies, and provide new insights into enhancing CAR-T cell efficacy in B-cell malignancies.
2024, 31(11):1051-1060.
Abstract:
Immunotherapy is propelling the field of anti-tumor treatment into a new era, with neoantigen vaccine serving as a pioneering force in immunotherapy. These vaccines are advancing their basic research and clinical trials at an unprecedented speed, yielding promising results and demonstrating substantial development potential. This review focuses on the latest progress in neoantigen vaccine research, with detailed introduction to the two major highlights: long peptide vaccines and mRNA vaccines. Peptide vaccines have attracted attention for their efficient production and scalability, though their rapid degradation poses a challenge. Advances in nanocarrier technologies help mitigate this limitation, and long-peptide vaccines have demonstrated promising efficacy in patients with various solid tumors, including melanoma and glioblastoma. Additionally, nanoparticle-based short peptide vaccines have demonstrated advantages in adjuvant gastric cancer therapy. mRNA vaccines, widely recognized for their application in COVID-19, have become a hotspot in cancer vaccine development due to their safety and ability to encode multiple antigens. For example, RNA vaccines encoding various KRAS mutations have shown favorable outcomes in pancreatic cancer. Furthermore, several studies suggest that combining neoantigen vaccines with immune checkpoint inhibitors or adoptive cell therapies can exert synergistic effects, further enhancing efficacy. This article delves into the challenges faced by neoantigen vaccines in the clinical translation phase and, based on this, actively explores and discusses potential strategies to address these challenges. The aim is to inspire new ideas and pave the way for future advancements in neoantigen vaccine development.
Immunotherapy is propelling the field of anti-tumor treatment into a new era, with neoantigen vaccine serving as a pioneering force in immunotherapy. These vaccines are advancing their basic research and clinical trials at an unprecedented speed, yielding promising results and demonstrating substantial development potential. This review focuses on the latest progress in neoantigen vaccine research, with detailed introduction to the two major highlights: long peptide vaccines and mRNA vaccines. Peptide vaccines have attracted attention for their efficient production and scalability, though their rapid degradation poses a challenge. Advances in nanocarrier technologies help mitigate this limitation, and long-peptide vaccines have demonstrated promising efficacy in patients with various solid tumors, including melanoma and glioblastoma. Additionally, nanoparticle-based short peptide vaccines have demonstrated advantages in adjuvant gastric cancer therapy. mRNA vaccines, widely recognized for their application in COVID-19, have become a hotspot in cancer vaccine development due to their safety and ability to encode multiple antigens. For example, RNA vaccines encoding various KRAS mutations have shown favorable outcomes in pancreatic cancer. Furthermore, several studies suggest that combining neoantigen vaccines with immune checkpoint inhibitors or adoptive cell therapies can exert synergistic effects, further enhancing efficacy. This article delves into the challenges faced by neoantigen vaccines in the clinical translation phase and, based on this, actively explores and discusses potential strategies to address these challenges. The aim is to inspire new ideas and pave the way for future advancements in neoantigen vaccine development.
2024, 31(11):1061-1072.
Abstract:
Immunotherapy has revolutionized clinical treatment of solid tumors, becoming a core strategy for the treatment of solid tumors. Currently approved immunotherapy strategies for solid tumors include PD-1 antibodies, CTLA-4 antibodies, bispecific antibodies, TCR-T cells, and TIL. These approaches primarily exert antitumor effects by activating T-cell-mediated immune responses or directly supplementing tumor-reactive T cells. However, restrained by inhibitory factors within the tumor microenvironment, the therapeutic outcomes of these strategies remain suboptimal. Based on the cancer-immunity cycle theory, this article provides a systematic review of approved immunotherapy strategies, early-stage clinical trials, and emerging immunotherapy approaches. It also offers insights into the future directions of immunotherapy targeting T cells and other cell populations beyond T cells.
Immunotherapy has revolutionized clinical treatment of solid tumors, becoming a core strategy for the treatment of solid tumors. Currently approved immunotherapy strategies for solid tumors include PD-1 antibodies, CTLA-4 antibodies, bispecific antibodies, TCR-T cells, and TIL. These approaches primarily exert antitumor effects by activating T-cell-mediated immune responses or directly supplementing tumor-reactive T cells. However, restrained by inhibitory factors within the tumor microenvironment, the therapeutic outcomes of these strategies remain suboptimal. Based on the cancer-immunity cycle theory, this article provides a systematic review of approved immunotherapy strategies, early-stage clinical trials, and emerging immunotherapy approaches. It also offers insights into the future directions of immunotherapy targeting T cells and other cell populations beyond T cells.
2024, 31(11):1073-1084.
Abstract:
Despite significant improvements in survival among lung cancer patients treated with PD-1/PD-L1 inhibitor-based immunotherapy, the issue of drug resistance remains a major challenge. This article delineates the definition, mechanisms, and predictive models of immunotherapy resistance, and introduces therapeutic strategies to address resistance, including continued use of immunotherapy, rechallenge, local treatment combined with systemic immunotherapy in the context of oligometastasis, and combination therapy after extensive progression. Furthermore, it explores the application prospects of novel therapeutic approaches such as adoptive cell therapy, antibody-drug conjugates, bispecific antibodies, and tumor vaccines in overcoming drug resistance. Additionally, the article summarizes the challenges and development directions of immunotherapy for lung cancer, emphasizing the importance of ongoing research, innovative treatment strategies, and interdisciplinary collaboration. These efforts aim to provide new ideas and research directions for achieving personalized, precise, and efficient lung cancer treatment in the future.
Despite significant improvements in survival among lung cancer patients treated with PD-1/PD-L1 inhibitor-based immunotherapy, the issue of drug resistance remains a major challenge. This article delineates the definition, mechanisms, and predictive models of immunotherapy resistance, and introduces therapeutic strategies to address resistance, including continued use of immunotherapy, rechallenge, local treatment combined with systemic immunotherapy in the context of oligometastasis, and combination therapy after extensive progression. Furthermore, it explores the application prospects of novel therapeutic approaches such as adoptive cell therapy, antibody-drug conjugates, bispecific antibodies, and tumor vaccines in overcoming drug resistance. Additionally, the article summarizes the challenges and development directions of immunotherapy for lung cancer, emphasizing the importance of ongoing research, innovative treatment strategies, and interdisciplinary collaboration. These efforts aim to provide new ideas and research directions for achieving personalized, precise, and efficient lung cancer treatment in the future.
2024, 31(11):1085-1091.
Abstract:
Nonsense-mediated mRNA decay (NMD) serves as a quality control mechanism, degrading aberrant mRNAs with premature termination codons (PTCs). It also plays a role in growth and development, immune regulation, and is closely associated with the tumor microenvironment. NMD has a dual role in cancer; on the one hand, it inhibits tumor progression through down-regulation of pro-oncogenic protein expression, inhibition of pro-oncogenic signaling pathways and stressful microenvironments, while one the other hand, it promotes tumor progression by inhibiting oncogene expression, cancer cell apoptosis and tumor neoantigen production. Notably, NMD does not degrade all PTC-containing mRNAs. The location of the PTC may determine whether NMD is triggered or evaded. Since different genes vary greatly in high-frequency mutation regions, the likelihood of triggering NMD after a PTC mutation differs across genes. With the maturation and widespread use of second-generation sequencing technology, gene mutation screening has become a routine clinical diagnostic tool, making it possible to explore the patterns and significance of NMD from a multi-gene perspective. By further understanding the functions and mechanisms of NMD and assessing the NMD levels through high-throughput sequencing and computational algorithms, its potential clinical value is expected to be revealed, contributing to the advancement of personalized treatment and precision medicine.
Nonsense-mediated mRNA decay (NMD) serves as a quality control mechanism, degrading aberrant mRNAs with premature termination codons (PTCs). It also plays a role in growth and development, immune regulation, and is closely associated with the tumor microenvironment. NMD has a dual role in cancer; on the one hand, it inhibits tumor progression through down-regulation of pro-oncogenic protein expression, inhibition of pro-oncogenic signaling pathways and stressful microenvironments, while one the other hand, it promotes tumor progression by inhibiting oncogene expression, cancer cell apoptosis and tumor neoantigen production. Notably, NMD does not degrade all PTC-containing mRNAs. The location of the PTC may determine whether NMD is triggered or evaded. Since different genes vary greatly in high-frequency mutation regions, the likelihood of triggering NMD after a PTC mutation differs across genes. With the maturation and widespread use of second-generation sequencing technology, gene mutation screening has become a routine clinical diagnostic tool, making it possible to explore the patterns and significance of NMD from a multi-gene perspective. By further understanding the functions and mechanisms of NMD and assessing the NMD levels through high-throughput sequencing and computational algorithms, its potential clinical value is expected to be revealed, contributing to the advancement of personalized treatment and precision medicine.
2024, 31(11):1092-1100.
Abstract:
Objective: To investigate the influence of SOX9 on the proliferation, migration, invasion, and stemness of laryngeal squamous cell carcinoma (LSCC) cells by upregulating the expression of long non-coding RNA LINC01503. Methods: Human LSCC cells AMC-HN-8, TU177, TU212, and TU686 were cultured routinely. Control nucleic acids (NC) and knockdown sequences (si-SOX9- NC, si-SOX9#1, si-SOX9#2, si-LINC01503-NC, si-LINC01503#1, si-LINC01503#2) or overexpression plasmids (pcDNA3.1-SOXNC, pcDNA3.1-SOX-oe, pcDNA3.1-LIN01503-NC, and pcDNA3.1-LIN01503-oe) were transfected into TU177 cells or TU686 cells. These groups were named as si-SOX9-NC group, si-SOX9#1 group, si-SOX9#2 group, si-LINC01503-NC group, si-LINC01503#1 group, si-LINC01503#2 group; pcDNA3.1-SOX9-NC group, pcDNA3.1-SOX9-oe group, pcDNA3.1-LINC01503-NC group, pcDNA3.1-LINC01503-oe group, si-SOX9-NC + pcDNA3.1-LINC01503-NC group, and si-SOX9 + pcDNA3.1-LINC01503-oe group. The expression of SOX9 mRNA and LINC01503 in each group of cells was detected by qPCR. Bioinformatics tool was employed to identify the binding site of SOX9 to lncRNA LINC01503 promoter region. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene experiments were carried out to validate the binding between SOX9 and the LINC01503 promoter. SOX9 knockdown efficiency and the influence of LINC01503 on the expression of stem cell markers in TU177 and TU686 cells were detected by WB assay. MTS assay was used to detect cell proliferation, scratch wound healing, and Transwell assays assessed cell migration, while colony formation assays evaluated the ability of cells to form colonies. Results: SOX9 was highly expressed in all LSCC cells (R = 0.12, P < 0.05). Database analysis showed a positive correlation between SOX9 and LINC01503 expression in head and neck squamous cell carcinoma (P = 0.005 9). It was proved that SOX9 directly binds with the LINC01503 promoter and promotes its transcriptional expression (P < 0.05). Knockdown of LINC01503 significantly suppressed the proliferation, migration, and invasion of TU177 cells (all P<0.05). Overexpression of LINC01503 notably enhanced the proliferation, migration, invasion and colony formation of TU686 cells (all P<0.05), as well as the expression of cell stemness markers CD133, OCT4, and SOX2 at both mRNA and protein levels (all P<0.05). However, knockdown of LINC01503 inhibited colony formation and expression of stem cell markers in TU686 cells (P < 0.05). Knockdown of SOX9 significantly suppressed the proliferation, migration, and invasion ability of TU177 cells and reduced the expression of their stem cell markers (all P<0.05). Meanwhile, overexpression of LINC01503 partially reversed the inhibitory effect of SOX9 knockdown on the malignant biological behavior and stem cell marker expression in TU177 cells (all P < 0.05). Conclusion: Both SOX9 and LINC01503 are highly expressed in LSCC cells. SOX9 may promote the proliferation, migration, invasion and stemness of laryngeal squamous cell carcinoma by upregulating LINC01503 expression.
Objective: To investigate the influence of SOX9 on the proliferation, migration, invasion, and stemness of laryngeal squamous cell carcinoma (LSCC) cells by upregulating the expression of long non-coding RNA LINC01503. Methods: Human LSCC cells AMC-HN-8, TU177, TU212, and TU686 were cultured routinely. Control nucleic acids (NC) and knockdown sequences (si-SOX9- NC, si-SOX9#1, si-SOX9#2, si-LINC01503-NC, si-LINC01503#1, si-LINC01503#2) or overexpression plasmids (pcDNA3.1-SOXNC, pcDNA3.1-SOX-oe, pcDNA3.1-LIN01503-NC, and pcDNA3.1-LIN01503-oe) were transfected into TU177 cells or TU686 cells. These groups were named as si-SOX9-NC group, si-SOX9#1 group, si-SOX9#2 group, si-LINC01503-NC group, si-LINC01503#1 group, si-LINC01503#2 group; pcDNA3.1-SOX9-NC group, pcDNA3.1-SOX9-oe group, pcDNA3.1-LINC01503-NC group, pcDNA3.1-LINC01503-oe group, si-SOX9-NC + pcDNA3.1-LINC01503-NC group, and si-SOX9 + pcDNA3.1-LINC01503-oe group. The expression of SOX9 mRNA and LINC01503 in each group of cells was detected by qPCR. Bioinformatics tool was employed to identify the binding site of SOX9 to lncRNA LINC01503 promoter region. Chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene experiments were carried out to validate the binding between SOX9 and the LINC01503 promoter. SOX9 knockdown efficiency and the influence of LINC01503 on the expression of stem cell markers in TU177 and TU686 cells were detected by WB assay. MTS assay was used to detect cell proliferation, scratch wound healing, and Transwell assays assessed cell migration, while colony formation assays evaluated the ability of cells to form colonies. Results: SOX9 was highly expressed in all LSCC cells (R = 0.12, P < 0.05). Database analysis showed a positive correlation between SOX9 and LINC01503 expression in head and neck squamous cell carcinoma (P = 0.005 9). It was proved that SOX9 directly binds with the LINC01503 promoter and promotes its transcriptional expression (P < 0.05). Knockdown of LINC01503 significantly suppressed the proliferation, migration, and invasion of TU177 cells (all P<0.05). Overexpression of LINC01503 notably enhanced the proliferation, migration, invasion and colony formation of TU686 cells (all P<0.05), as well as the expression of cell stemness markers CD133, OCT4, and SOX2 at both mRNA and protein levels (all P<0.05). However, knockdown of LINC01503 inhibited colony formation and expression of stem cell markers in TU686 cells (P < 0.05). Knockdown of SOX9 significantly suppressed the proliferation, migration, and invasion ability of TU177 cells and reduced the expression of their stem cell markers (all P<0.05). Meanwhile, overexpression of LINC01503 partially reversed the inhibitory effect of SOX9 knockdown on the malignant biological behavior and stem cell marker expression in TU177 cells (all P < 0.05). Conclusion: Both SOX9 and LINC01503 are highly expressed in LSCC cells. SOX9 may promote the proliferation, migration, invasion and stemness of laryngeal squamous cell carcinoma by upregulating LINC01503 expression.
2024, 31(11):1101-1108.
Abstract:
Objective: To investigate the expression of aryl hydrocarbon receptor (AHR) in breast cancer and its regulatory mechanisms in the proliferation, apoptosis, and drug sensitivity of breast cancer cells. Methods: The GEPIA database was used to analyze the expression levels of AHR in tumor tissues and adjacent normal tissues of breast cancer patients and explore its correlation with patient survival. Gene knockdown and overexpression techniques were employed to establish breast cancer cell lines with varying AHR expression levels. The impact of AHR on cell proliferation, apoptosis, and drug sensitivity was evaluated using CCK-8 assays, cell counting, and flow cytometry. The molecular mechanisms were validated through WB. Additionally, the effect of exogenous AHR activation using the AHR agonist 6-Formylindolo[3,2-b] carbazole (FICZ) on the doxorubicin (DOX) chemosensitivity of breast cancer was investigated. Results: GEPIA database analysis revealed a significant decrease in AHR expression in breast cancer tissues (P < 0.05); statistical analysis of the survival data from 155 breast cancer patients also indicated that low AHR expression was associated with poor prognosis (P < 0.05). AHR gene knockdown promoted cell proliferation (P < 0.05), while overexpression inhibited proliferation (P < 0.05) and promoted apoptosis (P < 0.05). Exogenous AHR activation enhanced the sensitivity of breast cancer cells to DOX (P < 0.05). AHR was found to bind to the MYC promoter, suppressing MYC expression, thereby influencing the progression of breast cancer. Conclusion: AHR regulates cell proliferation and apoptosis in breast cancer by modulating MYC expression. Exogenous activation of AHR may serve as a promising therapeutic strategy to enhance the sensitivity of breast cancer cells to DOX.
Objective: To investigate the expression of aryl hydrocarbon receptor (AHR) in breast cancer and its regulatory mechanisms in the proliferation, apoptosis, and drug sensitivity of breast cancer cells. Methods: The GEPIA database was used to analyze the expression levels of AHR in tumor tissues and adjacent normal tissues of breast cancer patients and explore its correlation with patient survival. Gene knockdown and overexpression techniques were employed to establish breast cancer cell lines with varying AHR expression levels. The impact of AHR on cell proliferation, apoptosis, and drug sensitivity was evaluated using CCK-8 assays, cell counting, and flow cytometry. The molecular mechanisms were validated through WB. Additionally, the effect of exogenous AHR activation using the AHR agonist 6-Formylindolo[3,2-b] carbazole (FICZ) on the doxorubicin (DOX) chemosensitivity of breast cancer was investigated. Results: GEPIA database analysis revealed a significant decrease in AHR expression in breast cancer tissues (P < 0.05); statistical analysis of the survival data from 155 breast cancer patients also indicated that low AHR expression was associated with poor prognosis (P < 0.05). AHR gene knockdown promoted cell proliferation (P < 0.05), while overexpression inhibited proliferation (P < 0.05) and promoted apoptosis (P < 0.05). Exogenous AHR activation enhanced the sensitivity of breast cancer cells to DOX (P < 0.05). AHR was found to bind to the MYC promoter, suppressing MYC expression, thereby influencing the progression of breast cancer. Conclusion: AHR regulates cell proliferation and apoptosis in breast cancer by modulating MYC expression. Exogenous activation of AHR may serve as a promising therapeutic strategy to enhance the sensitivity of breast cancer cells to DOX.
2024, 31(11):1109-1115.
Abstract:
To investigate the effect of total panax notoginseng saponin (PNS) on the survival of mouse melanoma B16-F10 cells by regulating macrophage polarization through JAK2/STAT3 pathway. Methods: B16-F10 cells and macrophage RAW264.7 were cultured regularly. The effects of different concentrations of PNS on the survival rate of RAW264.7 or B16-F10 cells were detected by MTT assay. The experiment was divided into the following groups: blank group (B16-F10 cells only), control group (B16-F10 cells cocultured with RAW264.7 cells), PNS groups of various concentrations (B16-F10 cells co-cultured with RAW 264.7 cells, treated with 50, 100, 200 μg/mL PNS), and PNS + colivelin [B16-F10 cells co-cultured with RAW264.7 cells, 200 μg/mL PNS, 0.5 μmol/L colivelin (JAK2/STAT3 pathway activator)] group. MTT assay and flow cytometry were applied to detect the survival rate and apoptosis rate of co-cultured cells in each group, and the morphological changes of macrophages were observed under a microscope. ELISA was applied to detect the levels of cytokines TNF- α, IL-6 and IL-1β in the supernatant. qPCR was applied to detect the mRNA expression of macrophage polarization-related genes, inducible nitric oxide synthase (iNOS), IL-12, CD206, and arginase-1 (Arg-1). Western blotting was applied to detect the phosphorylation levels of JAK2 and STAT3 proteins pathway in cells. Results: PNS of different concentrations did not significantly affect the viability of RAW264.7 cells or B16-F10 cells cultured alone (all P > 0.05). Compared with the control group, PNS significantly promoted cell apoptosis, protein levels of IL-6, TNF-α, IL-1β, and mRNA levels of IL-12 and iNOS in a concentration-dependent manner (all P < 0.05); additionally, PNS reduced the survival rate of co-cultured cells and the phosphorylation levels of JAK2 and STAT3 proteins (all P < 0.05). These effects of PNS on co-cultured cells were partially inhibited by colivelin. Conclusion: PNS inhibits the viability of mouse melanoma B16-F10 cells by promoting the polarization of M1 macrophages via inhibiting JAK2/STAT3 pathway.
To investigate the effect of total panax notoginseng saponin (PNS) on the survival of mouse melanoma B16-F10 cells by regulating macrophage polarization through JAK2/STAT3 pathway. Methods: B16-F10 cells and macrophage RAW264.7 were cultured regularly. The effects of different concentrations of PNS on the survival rate of RAW264.7 or B16-F10 cells were detected by MTT assay. The experiment was divided into the following groups: blank group (B16-F10 cells only), control group (B16-F10 cells cocultured with RAW264.7 cells), PNS groups of various concentrations (B16-F10 cells co-cultured with RAW 264.7 cells, treated with 50, 100, 200 μg/mL PNS), and PNS + colivelin [B16-F10 cells co-cultured with RAW264.7 cells, 200 μg/mL PNS, 0.5 μmol/L colivelin (JAK2/STAT3 pathway activator)] group. MTT assay and flow cytometry were applied to detect the survival rate and apoptosis rate of co-cultured cells in each group, and the morphological changes of macrophages were observed under a microscope. ELISA was applied to detect the levels of cytokines TNF- α, IL-6 and IL-1β in the supernatant. qPCR was applied to detect the mRNA expression of macrophage polarization-related genes, inducible nitric oxide synthase (iNOS), IL-12, CD206, and arginase-1 (Arg-1). Western blotting was applied to detect the phosphorylation levels of JAK2 and STAT3 proteins pathway in cells. Results: PNS of different concentrations did not significantly affect the viability of RAW264.7 cells or B16-F10 cells cultured alone (all P > 0.05). Compared with the control group, PNS significantly promoted cell apoptosis, protein levels of IL-6, TNF-α, IL-1β, and mRNA levels of IL-12 and iNOS in a concentration-dependent manner (all P < 0.05); additionally, PNS reduced the survival rate of co-cultured cells and the phosphorylation levels of JAK2 and STAT3 proteins (all P < 0.05). These effects of PNS on co-cultured cells were partially inhibited by colivelin. Conclusion: PNS inhibits the viability of mouse melanoma B16-F10 cells by promoting the polarization of M1 macrophages via inhibiting JAK2/STAT3 pathway.
2024, 31(11):1116-1122.
Abstract:
Objective: To investigate the radioprotective effects of the fusion antioxidant enzyme GST-SOD1-X-R9 (GS1XR) on normal nasopharyngeal epithelial cells (NP69) and its potential mechanisms. Methods: NP69 cells were cultured and divided into the following groups: untreated control (Untr) group, EGFP-GS1 group, EGFP-GS1R group, and EGFP-GS1XR group. The transmembrane effect of different fusion antioxidant enzymes was evaluated at a concentration of 0.5 mg/mL. The cytotoxicity of the three enzymes within a concentration range of 0 to 1 mg/mL was determined using the CCK-8 assay. ROS levels in NP69 cells were measured using a DCFH-DA fluorescent probe following exposure to 0～6 Gy X-ray and varying doses (0～1 mg/mL) of GS1XR. In further experiments, NP69 cells were divided into blank control (Untr) group, 4 Gy X-ray only group (Ctrl), and groups pre-treated with GS1, GS1R, GS1XR, or Amifostine (AMFT, 4 μg/mL) before X-ray exposure. ROS levels, apoptosis rate, Nrf2 nuclear translocation, and expression of antioxidant gene GCLC, anti-apoptotic factor Bcl-2, and pro-apoptotic factor BAX were evaluated using flow cytometry and WB analysis. Results: EGFP-GS1 lacked transmembrane ability, whereas EGFP-GS1R and EGFP-GS1XR efficiently crossed the NP69 cell membrane (P < 0.000 1). After 24 hours of treatment, all three fusion antioxidant enzymes maintained cell viability above 80%, with the GS1XR-treated group maintaining cell viability above 100%. Exposure to 4 Gy X-ray significantly increased intracellular ROS levels (P < 0.01), while GS1XR effectively reduced radiation-induced ROS in a dose-dependent manner. Compared to the Ctrl group, GS1XR significantly decreased intracellular ROS levels (P < 0.05), promoted Nrf2 nuclear translocation (P < 0.01), upregulated the expression of antioxidant gene GCLC (P < 0.000 1), and reduced the apoptosis rate (P < 0.000 1). Additionally, it increased the expression of anti-apoptotic factor Bcl-2 (P < 0.001) and downregulated pro-apoptotic factor BAX (P < 0.05). The overall protective effects of GS1XR were similar to those of GS1R and comparable to the effects of Amifostine. Conclusion: The fusion antioxidant enzyme GS1XR exhibits significant radioprotective effects on NP69 cells, likely through its ability to enter cells, eliminate radiation-induced ROS, activate the Nrf2 signaling pathway, and regulate the expression of Bcl-2 and BAX. GS1XR shows potential as a novel radioprotective agent.
Objective: To investigate the radioprotective effects of the fusion antioxidant enzyme GST-SOD1-X-R9 (GS1XR) on normal nasopharyngeal epithelial cells (NP69) and its potential mechanisms. Methods: NP69 cells were cultured and divided into the following groups: untreated control (Untr) group, EGFP-GS1 group, EGFP-GS1R group, and EGFP-GS1XR group. The transmembrane effect of different fusion antioxidant enzymes was evaluated at a concentration of 0.5 mg/mL. The cytotoxicity of the three enzymes within a concentration range of 0 to 1 mg/mL was determined using the CCK-8 assay. ROS levels in NP69 cells were measured using a DCFH-DA fluorescent probe following exposure to 0～6 Gy X-ray and varying doses (0～1 mg/mL) of GS1XR. In further experiments, NP69 cells were divided into blank control (Untr) group, 4 Gy X-ray only group (Ctrl), and groups pre-treated with GS1, GS1R, GS1XR, or Amifostine (AMFT, 4 μg/mL) before X-ray exposure. ROS levels, apoptosis rate, Nrf2 nuclear translocation, and expression of antioxidant gene GCLC, anti-apoptotic factor Bcl-2, and pro-apoptotic factor BAX were evaluated using flow cytometry and WB analysis. Results: EGFP-GS1 lacked transmembrane ability, whereas EGFP-GS1R and EGFP-GS1XR efficiently crossed the NP69 cell membrane (P < 0.000 1). After 24 hours of treatment, all three fusion antioxidant enzymes maintained cell viability above 80%, with the GS1XR-treated group maintaining cell viability above 100%. Exposure to 4 Gy X-ray significantly increased intracellular ROS levels (P < 0.01), while GS1XR effectively reduced radiation-induced ROS in a dose-dependent manner. Compared to the Ctrl group, GS1XR significantly decreased intracellular ROS levels (P < 0.05), promoted Nrf2 nuclear translocation (P < 0.01), upregulated the expression of antioxidant gene GCLC (P < 0.000 1), and reduced the apoptosis rate (P < 0.000 1). Additionally, it increased the expression of anti-apoptotic factor Bcl-2 (P < 0.001) and downregulated pro-apoptotic factor BAX (P < 0.05). The overall protective effects of GS1XR were similar to those of GS1R and comparable to the effects of Amifostine. Conclusion: The fusion antioxidant enzyme GS1XR exhibits significant radioprotective effects on NP69 cells, likely through its ability to enter cells, eliminate radiation-induced ROS, activate the Nrf2 signaling pathway, and regulate the expression of Bcl-2 and BAX. GS1XR shows potential as a novel radioprotective agent.
RAN Xiaoke
,
LIU Xudong
,
TAN Weiqiang
,
PANG Huazhen
,
YUAN Yuan
,
LOU Xinfeng
,
WU Tiexiong
,
PAN Zhaoquan
2024, 31(11):1123-1130.
Abstract:
Objective: To explore the role and mechanism of CXC chemokine ligand 5/CXC receptor 2/ vascular endothelial growth factor (CXCL5/CXCR2/VEGF) pathway in the angiogenesis of hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). Methods: Peripheral blood samples were collected from 10 HBV-DNA positive patients admitted to Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine between October 2022 and December 2022, including 5 cases of HCC and 5 cases of liver cirrhosis (LC). High-throughput RNA sequencing was used to detect and screen differentially expressed mRNAs. GO enrichment and KEGG pathway analysis were conducted to explore the biological functions and related signaling pathways of these differentially expressed genes. HCC HepG2 cells were conventionally cultured, and CXCL5 overexpression plasmid and control plasmid were transfected into HepG2 cells using transfection reagents. The cells were divided into a control group, an empty load group, and two CXCL5 overexpression groups (250 ng/mL and 520 ng/mL). The effects of CXCL5 overexpression on HepG2 cell proliferation (CCK-8 method), VEGF secretion (ELISA), tube formation ability (angiogenesis assay), mRNA and protein expression of CXCL5, CXCR2, VEGF (qPCR, Western blot), as well as VEGF expression immunofluorescence intensity were analyzed. Results: RNA sequencing results showed significant differences in mRNA expression in peripheral blood between HCC and LC patients. GO enrichment analysis revealed that these differentially expressed genes were mainly involved in cell development regulation, G proteincoupled receptor activity, extracellular region components, and receptor-ligand binding. KEGG pathway analysis revealed that these differentially expressed genes might participate in pathways related to the cytokine-receptor interactions, cAMP signaling and other cancer related pathways, neuroactive ligand-receptor interactions, and calcium signaling pathways. Overexpression of CXCL5 significantly promoted HepG2 cell proliferation (P < 0.05), VEGF secretion (P < 0.05), tube formation in human umbilical vein endothelial cells (HUVECs) (P < 0.05), and mRNA and protein expression of CXCL5, CXCR2, and VEGF (P < 0.05 or P < 0.01), as well as enhanced the immunofluorescence intensity of VEGF in HepG2 cells. Conclusion: CXCL5 may promote the proliferation of HepG2 cells and HUVEC angiogenesis through the CXCL5/CXCR2/VEGF axis.
Objective: To explore the role and mechanism of CXC chemokine ligand 5/CXC receptor 2/ vascular endothelial growth factor (CXCL5/CXCR2/VEGF) pathway in the angiogenesis of hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC). Methods: Peripheral blood samples were collected from 10 HBV-DNA positive patients admitted to Ruikang Hospital Affiliated to Guangxi University of Traditional Chinese Medicine between October 2022 and December 2022, including 5 cases of HCC and 5 cases of liver cirrhosis (LC). High-throughput RNA sequencing was used to detect and screen differentially expressed mRNAs. GO enrichment and KEGG pathway analysis were conducted to explore the biological functions and related signaling pathways of these differentially expressed genes. HCC HepG2 cells were conventionally cultured, and CXCL5 overexpression plasmid and control plasmid were transfected into HepG2 cells using transfection reagents. The cells were divided into a control group, an empty load group, and two CXCL5 overexpression groups (250 ng/mL and 520 ng/mL). The effects of CXCL5 overexpression on HepG2 cell proliferation (CCK-8 method), VEGF secretion (ELISA), tube formation ability (angiogenesis assay), mRNA and protein expression of CXCL5, CXCR2, VEGF (qPCR, Western blot), as well as VEGF expression immunofluorescence intensity were analyzed. Results: RNA sequencing results showed significant differences in mRNA expression in peripheral blood between HCC and LC patients. GO enrichment analysis revealed that these differentially expressed genes were mainly involved in cell development regulation, G proteincoupled receptor activity, extracellular region components, and receptor-ligand binding. KEGG pathway analysis revealed that these differentially expressed genes might participate in pathways related to the cytokine-receptor interactions, cAMP signaling and other cancer related pathways, neuroactive ligand-receptor interactions, and calcium signaling pathways. Overexpression of CXCL5 significantly promoted HepG2 cell proliferation (P < 0.05), VEGF secretion (P < 0.05), tube formation in human umbilical vein endothelial cells (HUVECs) (P < 0.05), and mRNA and protein expression of CXCL5, CXCR2, and VEGF (P < 0.05 or P < 0.01), as well as enhanced the immunofluorescence intensity of VEGF in HepG2 cells. Conclusion: CXCL5 may promote the proliferation of HepG2 cells and HUVEC angiogenesis through the CXCL5/CXCR2/VEGF axis.
2024, 31(11):1131-1135.
Abstract:
Objective: To investigate the effects of anti-programmed death 1 (PD-1) immunotherapy on the prognosis of patients with non-small cell lung cancer (NSCLC) complicated with cachexia. Methods: A total of 80 patients with cachexia associated with NSCLC, treated at Xijing Hospital between January 2019 and January 2021, were enrolled in this study. These patients were divided into two groups using a random number table: a control group and an observation group. The control group was given sequential chemoradiotherapy and other symptomatic treatments, as well as nutritional therapy. The observation group was treated with combined anti-PD-1 antibody immunotherapy. Clinical efficacy and improvement in physical condition were compared between the two groups. Pulmonary function and immune function in patients were observed before and after treatment. The patients were followed up for one year after treatment, and their cumulative 1-year survival rate was calculated. Results: There were no significant differences in disease control rate (DCR) and objective response rate (ORR) between the two groups of NSCLC patients (all P > 0.05). However, compared with the control group, the observation group showed significantly higher appetite score, Karnofsky performance status (KPS) score, and higher proportions of CD3+ and CD4+ /CD8+ lymphocyte subsets (all P < 0.05); additionally, the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the observation group were also higher than those in control group (all P < 0.05). At the 1-year follow-up, the survival rate in observation group was significantly higher than that in the control group (62.50% vs 40.00%, P < 0.05). Conclusion: Anti-PD-1 antibody immunotherapy can alleviate immune dysfunction and pulmonary function impairment in NSCLC patients with cachexia, and it significantly improves the 1-year survival rate of these patients.
Objective: To investigate the effects of anti-programmed death 1 (PD-1) immunotherapy on the prognosis of patients with non-small cell lung cancer (NSCLC) complicated with cachexia. Methods: A total of 80 patients with cachexia associated with NSCLC, treated at Xijing Hospital between January 2019 and January 2021, were enrolled in this study. These patients were divided into two groups using a random number table: a control group and an observation group. The control group was given sequential chemoradiotherapy and other symptomatic treatments, as well as nutritional therapy. The observation group was treated with combined anti-PD-1 antibody immunotherapy. Clinical efficacy and improvement in physical condition were compared between the two groups. Pulmonary function and immune function in patients were observed before and after treatment. The patients were followed up for one year after treatment, and their cumulative 1-year survival rate was calculated. Results: There were no significant differences in disease control rate (DCR) and objective response rate (ORR) between the two groups of NSCLC patients (all P > 0.05). However, compared with the control group, the observation group showed significantly higher appetite score, Karnofsky performance status (KPS) score, and higher proportions of CD3+ and CD4+ /CD8+ lymphocyte subsets (all P < 0.05); additionally, the forced expiratory volume in 1 second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC) in the observation group were also higher than those in control group (all P < 0.05). At the 1-year follow-up, the survival rate in observation group was significantly higher than that in the control group (62.50% vs 40.00%, P < 0.05). Conclusion: Anti-PD-1 antibody immunotherapy can alleviate immune dysfunction and pulmonary function impairment in NSCLC patients with cachexia, and it significantly improves the 1-year survival rate of these patients.
2024, 31(11):1136-1145.
Abstract:
Objective: To evaluate the efficacy and potential adverse effects of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) [TT] with or without PD-1 antibody (PD-1Ab) (TT + PD-1Ab vs TT alone) in the treatment of advanced hepatocellular carcinoma (aHCC). Methods: A literature search was conducted across PubMed, CNKI, Embase, and Web of Science from database inception to January 31, 2024. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Meta-analysis was performed using Stata16.0 software. Results: A total of 17 studies involving 2 334 patients were included. The meta-analysis results showed that: Compared with TT therapy, the addition of PD-1 antibody significantly improved overall survival [HR = 0.44, 95% CI (0.36, 0.51), P < 0.000 01 ], progression-free survival[HR = 0.47, 95% CI (0.42, 0.52), P < 0.000 01], objective response rate (ORR) [HR = 1.65, 95% CI (1.46, 1.86), P < 0.000 01], and disease control rate (DCR) (HR = 1.26, 95% CI [1.15, 1.38], P < 0.000 01); aHCC patients with different baseline characteristics such as ECOG-PS, extrahepatic metastasis, BCLC stage, tumor size, Child-Pugh score, and hepatic portal vein invasion benefited from TT + PD-1Ab therapy; There was no significant difference in the overall incidence of all-grades and ≥ grade 3 adverse events (AEs) between the two regimens, but symptoms such as hypertension, hypothyroidism, and reactive cutaneous vascular proliferation were more common in patients treated with TT + PD-1Ab. Conclusion: Compared with the TT therapy, the addition of PD-1Ab can significantly extend OS and PFS and improve the ORR and DCR in patients with aHCC. The overall incidence of all-grades and ≥ grade 3 AEs was not significantly increased in the TT PD-1 Ab group, with good overall tolerability, although higher rates of hypertension, mucocutaneous, and thyroidrelated AEs were observed in the TT + PD-1Ab group and should be closely monitored.
Objective: To evaluate the efficacy and potential adverse effects of transarterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) [TT] with or without PD-1 antibody (PD-1Ab) (TT + PD-1Ab vs TT alone) in the treatment of advanced hepatocellular carcinoma (aHCC). Methods: A literature search was conducted across PubMed, CNKI, Embase, and Web of Science from database inception to January 31, 2024. Two reviewers independently screened literature, extracted data, and assessed the risk of bias of included studies. Meta-analysis was performed using Stata16.0 software. Results: A total of 17 studies involving 2 334 patients were included. The meta-analysis results showed that: Compared with TT therapy, the addition of PD-1 antibody significantly improved overall survival [HR = 0.44, 95% CI (0.36, 0.51), P < 0.000 01 ], progression-free survival[HR = 0.47, 95% CI (0.42, 0.52), P < 0.000 01], objective response rate (ORR) [HR = 1.65, 95% CI (1.46, 1.86), P < 0.000 01], and disease control rate (DCR) (HR = 1.26, 95% CI [1.15, 1.38], P < 0.000 01); aHCC patients with different baseline characteristics such as ECOG-PS, extrahepatic metastasis, BCLC stage, tumor size, Child-Pugh score, and hepatic portal vein invasion benefited from TT + PD-1Ab therapy; There was no significant difference in the overall incidence of all-grades and ≥ grade 3 adverse events (AEs) between the two regimens, but symptoms such as hypertension, hypothyroidism, and reactive cutaneous vascular proliferation were more common in patients treated with TT + PD-1Ab. Conclusion: Compared with the TT therapy, the addition of PD-1Ab can significantly extend OS and PFS and improve the ORR and DCR in patients with aHCC. The overall incidence of all-grades and ≥ grade 3 AEs was not significantly increased in the TT PD-1 Ab group, with good overall tolerability, although higher rates of hypertension, mucocutaneous, and thyroidrelated AEs were observed in the TT + PD-1Ab group and should be closely monitored.
2024, 31(11):1146-1151.
Abstract:
[摘要] 转移靶器官中休眠的播散肿瘤细胞（DTC）增殖是导致癌症早期根治术后患者临床转移和死亡的关键，因此靶向根除休 眠DTC是防止肿瘤转移的重要治疗策略之一，但目前仍缺乏特异性的治疗药物。通过调控NK细胞和CD8+ T细胞等免疫细胞清 除休眠的DTC；靶向抑制细胞存活通路（MAPK和PI3K/AKT/mTOR等）根除休眠DTC；靶向线粒体氧化磷酸化能量代谢途径抑 制休眠DTC的存活；羟氯喹靶向抑制细胞自噬或过度激活细胞自噬诱导休眠DTC凋亡等，都可能开发出具有靶向杀伤休眠DTC 进而防止肿瘤转移的治疗药物。本文聚焦可靶向根除休眠DTC的潜在治疗药物，以期推动抗肿瘤转移药物的临床转化效率，进 而提高癌症患者的临床疗效。
[摘要] 转移靶器官中休眠的播散肿瘤细胞（DTC）增殖是导致癌症早期根治术后患者临床转移和死亡的关键，因此靶向根除休 眠DTC是防止肿瘤转移的重要治疗策略之一，但目前仍缺乏特异性的治疗药物。通过调控NK细胞和CD8+ T细胞等免疫细胞清 除休眠的DTC；靶向抑制细胞存活通路（MAPK和PI3K/AKT/mTOR等）根除休眠DTC；靶向线粒体氧化磷酸化能量代谢途径抑 制休眠DTC的存活；羟氯喹靶向抑制细胞自噬或过度激活细胞自噬诱导休眠DTC凋亡等，都可能开发出具有靶向杀伤休眠DTC 进而防止肿瘤转移的治疗药物。本文聚焦可靶向根除休眠DTC的潜在治疗药物，以期推动抗肿瘤转移药物的临床转化效率，进 而提高癌症患者的临床疗效。
2024, 31(11):1152-1158.
Abstract:
[摘 要] 免疫检查点抑制剂（ICI）作为一种新型的肿瘤治疗药物，在一定程度上表现出良好的抗肿瘤活性，但也存在着诸多不 足之处，如易导致免疫相关不良反应、耐药性等问题。近年来的研究发现，天然黄酮类化合物不仅可以通过NF-κB、IFN-γ/JAK/ STAT和PI3K/AKT等多条信号通路下调免疫检查点分子的表达，还能与免疫检查点分子结合以阻断程序性死亡蛋白受体-1 （PD-1）和程序性死亡配体-1（PD-L1）之间的相互作用达到抗肿瘤目的，并且在与免疫检查点抑制剂的联合应用中表现出显著的 协同作用。由此可见，天然黄酮类化合物可能是一类很有潜力的ICI或免疫调节剂，且可能成为一个备受关注的研究方向，这为 肿瘤免疫治疗提供了新的思路和方向。
[摘 要] 免疫检查点抑制剂（ICI）作为一种新型的肿瘤治疗药物，在一定程度上表现出良好的抗肿瘤活性，但也存在着诸多不 足之处，如易导致免疫相关不良反应、耐药性等问题。近年来的研究发现，天然黄酮类化合物不仅可以通过NF-κB、IFN-γ/JAK/ STAT和PI3K/AKT等多条信号通路下调免疫检查点分子的表达，还能与免疫检查点分子结合以阻断程序性死亡蛋白受体-1 （PD-1）和程序性死亡配体-1（PD-L1）之间的相互作用达到抗肿瘤目的，并且在与免疫检查点抑制剂的联合应用中表现出显著的 协同作用。由此可见，天然黄酮类化合物可能是一类很有潜力的ICI或免疫调节剂，且可能成为一个备受关注的研究方向，这为 肿瘤免疫治疗提供了新的思路和方向。
2024, 31(11):1159-1162.
Abstract:
[摘 要] 皮肤免疫相关不良反应是免疫检查点抑制剂（ICI）使用过程中最常见的不良反应（AE）之一。目前，对于严重的AE具 体机制还不十分明确，如何预测严重皮肤AE也无合适方法。本报道观察到2例HLA-B*1502阴性患者在使用ICI联合卡马西平 治疗后出现严重皮疹，通过皮肤活检镜下见皮下有大量淋巴细胞浸润，以CD3+ T、CD4+ T和CD8+ T淋巴细胞为主，荧光显微镜下 无补体C3沉积。卡马西平所致皮疹机制也与T细胞免疫增强有关，提示ICI与卡马西平联合使用可能增加严重皮疹的发生，目 前未见文献报道。此2例患者经过皮质醇激素等积极治疗，最终皮肤毒性得以控制，本文通过对2例患者临床病程、诊疗、机制等 进行分析，以期为临床后续用药安全提供参考，避免严重皮肤AE的发生。
[摘 要] 皮肤免疫相关不良反应是免疫检查点抑制剂（ICI）使用过程中最常见的不良反应（AE）之一。目前，对于严重的AE具 体机制还不十分明确，如何预测严重皮肤AE也无合适方法。本报道观察到2例HLA-B*1502阴性患者在使用ICI联合卡马西平 治疗后出现严重皮疹，通过皮肤活检镜下见皮下有大量淋巴细胞浸润，以CD3+ T、CD4+ T和CD8+ T淋巴细胞为主，荧光显微镜下 无补体C3沉积。卡马西平所致皮疹机制也与T细胞免疫增强有关，提示ICI与卡马西平联合使用可能增加严重皮疹的发生，目 前未见文献报道。此2例患者经过皮质醇激素等积极治疗，最终皮肤毒性得以控制，本文通过对2例患者临床病程、诊疗、机制等 进行分析，以期为临床后续用药安全提供参考，避免严重皮肤AE的发生。
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Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
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Chinese Journal Of Cancer Biotheray ® 2025 All Rights Reserved
Supported by:Beijing E-Tiller Technology Development Co., Ltd.