2023 Vol.35(3)
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2023, 35(3): 197-232.
doi: 10.21147/j.issn.1000-9604.2023.03.01
Abstract
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Abstract:
2023, 35(3): 233-238.
doi: 10.21147/j.issn.1000-9604.2023.03.02
Abstract:
2023, 35(3): 239-244.
doi: 10.21147/j.issn.1000-9604.2023.03.03
Abstract:
Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors. Remarkable clinical success has been achieved in chimeric antigen receptor (CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies. However, many challenges such as resistance, antigen heterogeneity, poor immune cell infiltration, immunosuppressive microenvironment, metabolic obstructive microenvironment, and T cell exhaustion remain as barriers to broader application especially in solid tumors. Encouragingly, the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers. Here, in this perspective, we focus on the most recent clinical advancements, challenges, and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy, to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.
Adoptive cellular therapy is rapidly improving immunotherapy in hematologic malignancies and several solid tumors. Remarkable clinical success has been achieved in chimeric antigen receptor (CAR)-T cell therapy which represents a paradigm-shifting strategy for the treatment of hematological malignancies. However, many challenges such as resistance, antigen heterogeneity, poor immune cell infiltration, immunosuppressive microenvironment, metabolic obstructive microenvironment, and T cell exhaustion remain as barriers to broader application especially in solid tumors. Encouragingly, the development of new approaches such as multidimensional omics and biomaterials technologies was aided to overcome these barriers. Here, in this perspective, we focus on the most recent clinical advancements, challenges, and strategies of immune cellular therapy in solid tumor treatment represented by CAR-T cell therapy, to provide new ideas to further overcome the bottleneck of immune cell therapy and anticipate future clinical advances.
2023, 35(3): 245-251.
doi: 10.21147/j.issn.1000-9604.2023.03.04
Abstract:
Co-expression of immune checkpoint (IC) molecules can exacerbate T cell exhaustion in patients with hematological malignancies (HMs) and contribute to the immune escape of tumor cells, which is related to poor clinical outcome. It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome. In this perspective, we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs, providing new insights for designing dual IC blockades (ICBs).
Co-expression of immune checkpoint (IC) molecules can exacerbate T cell exhaustion in patients with hematological malignancies (HMs) and contribute to the immune escape of tumor cells, which is related to poor clinical outcome. It is worth establishing and optimizing an ideal prediction model based on the co-expression patterns of IC molecules to evaluate the immune status of HM patients and predict their clinical outcome. In this perspective, we summarize the co-expression patterns of IC molecules and their importance as biomarkers that predict the prognosis of patients with different HMs, providing new insights for designing dual IC blockades (ICBs).
2023, 35(3): 252-265.
doi: 10.21147/j.issn.1000-9604.2023.03.05
Abstract:
In recent years, immune checkpoint blockade (ICB) therapy has become an important treatment strategy for gastrointestinal tumors, however, it only benefits about 1/3 of patients. Since the microbiome has been shown to play an important role in the human body for a long time, a growing number of studies are focusing on its relationship to ICB therapy in cancer, specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors (ICIs) therapy in patients. On this basis, probiotic interventions, fecal microbiota transplantation (FMT), dietary interventions, and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention. This article discusses the four aspects of the microbiome, ICB, combined treatment of gastrointestinal tumors, and regulation of gut microbiome. Particularly, the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects (irAEs).
In recent years, immune checkpoint blockade (ICB) therapy has become an important treatment strategy for gastrointestinal tumors, however, it only benefits about 1/3 of patients. Since the microbiome has been shown to play an important role in the human body for a long time, a growing number of studies are focusing on its relationship to ICB therapy in cancer, specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors (ICIs) therapy in patients. On this basis, probiotic interventions, fecal microbiota transplantation (FMT), dietary interventions, and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention. This article discusses the four aspects of the microbiome, ICB, combined treatment of gastrointestinal tumors, and regulation of gut microbiome. Particularly, the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects (irAEs).
2023, 35(3): 266-282.
doi: 10.21147/j.issn.1000-9604.2023.03.06
Abstract:
Primary liver cancer is a significant health problem worldwide. Hepatocellular carcinoma (HCC) is the main pathological type of primary liver cancer, accounting for 75%−85% of cases. In recent years, radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC. However, radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors. How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration. This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy, including epigenetics, transportation and metabolism, regulated cell death pathways, the microenvironment, and redox status, as well as the effect of nanoparticles on the radiosensitivity of liver cancer. It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.
Primary liver cancer is a significant health problem worldwide. Hepatocellular carcinoma (HCC) is the main pathological type of primary liver cancer, accounting for 75%−85% of cases. In recent years, radiotherapy has become an emerging treatment for HCC and is effective for various stages of HCC. However, radiosensitivity of liver cancer cells has a significant effect on the efficacy of radiotherapy and is regulated by various factors. How to increase radiosensitivity and improve the therapeutic effects of radiotherapy require further exploration. This review summarizes the recent research progress on the mechanisms affecting sensitivity to radiotherapy, including epigenetics, transportation and metabolism, regulated cell death pathways, the microenvironment, and redox status, as well as the effect of nanoparticles on the radiosensitivity of liver cancer. It is expected to provide more effective strategies and methods for clinical treatment of liver cancer by radiotherapy.
2023, 35(3): 283-298.
doi: 10.21147/j.issn.1000-9604.2023.03.07
Abstract:
Natural killer (NK) cells can elicit an immune response against malignantly transformed cells without recognizing antigens, and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy. Although several studies have shown the promising antitumor effects of NK cells in immunotherapy, their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death. Thus, for efficient tumor immunotherapy, the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood. Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered. In this review, we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression [NKG2A, programmed cell death 1 (PD-1), and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif (TIGIT)] on the NK cell surface, and thus inhibit NK cell activity. We also reviewed the current status of treatments based on these surface molecules. By comparing the therapeutic effects related to the treatment status and bypass mechanisms, we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
Natural killer (NK) cells can elicit an immune response against malignantly transformed cells without recognizing antigens, and they also exhibit cytotoxic effects and immune surveillance functions in tumor immunotherapy. Although several studies have shown the promising antitumor effects of NK cells in immunotherapy, their function is often limited in the tumor microenvironment because tumor cells can easily escape NK cell-induced death. Thus, for efficient tumor immunotherapy, the mechanism by which tumor cells escape NK cell-induced cytotoxicity must be fully understood. Various novel molecules and checkpoint receptors that mediate the disruption of NK cells in the tumor microenvironment have been discovered. In this review, we analyze and detail the major activating and inhibitory receptors on the surface of NK cells to delineate the mechanism by which tumor cells suppress NKG2D ligand expression and increase tumor receptor and inhibitory receptor expression [NKG2A, programmed cell death 1 (PD-1), and T-cell immunoglobulin and immunoreceptor tyrosine inhibitory motif (TIGIT)] on the NK cell surface, and thus inhibit NK cell activity. We also reviewed the current status of treatments based on these surface molecules. By comparing the therapeutic effects related to the treatment status and bypass mechanisms, we attempt to identify optimal single or combined treatments to suggest new treatment strategies for tumor immunotherapy.
2023, 35(3): 299-315.
doi: 10.21147/j.issn.1000-9604.2023.03.08
Abstract:
ObjectiveCancer immunotherapy has made remarkable advances in recent years, but its effectiveness in treating gastric cancer is often limited by the complexity of the tumor microenvironment and the lack of effective biomarkers. This study aimed to identify effective biomarkers for immunotherapy treatment by characterizing the tumor microenvironment. MethodsWe retrieved the RNA-seq data from gastric cancer patients treated with the programmed death 1 (PD-1) blockade pembrolizumab. Differentially expressed genes associated with clinical outcomes were identified and further analyzed using gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Gene signature scores were calculated by single sample Gene Set Enrichment Analysis (ssGSEA). The infiltration levels of immune cells were quantified using the xCell website. Cell type enrichment analysis was performed to compare treatment response and non-response groups, and regression analysis was used to investigate the relationship between interferon gamma (IFNγ) immune response and immune cell infiltration. Biomarkers were identified using least absolute shrinkage and selection operator (LASSO) analysis. ResultsCompared to normal tissues, cytokine activity and interleukin-6 production were highly activated in gastric tumors. Responders to pembrolizumab showed significantly up-regulated expression of IFNγ response-related genes. Cell type enrichment analysis revealed that Th1 cells were significantly enriched in the tumor microenvironment of responders. Regression analysis indicated that Th1 cells induced IFNγ response more efficiently than other cell types. Using signatures of Th1 cells, stromal cells and IFNγ response, a set of eight genes were identified that effectively predicted the efficacy of immunotherapy treatment and patient prognosis. ConclusionsTh1 cells promote therapeutic efficacy of PD-1 blockade by promoting IFNγ immune response in gastric cancer. The identified biomarkers have the potential to improve the effectiveness of immunotherapy treatment for gastric cancer patients.
2023, 35(3): 316-330.
doi: 10.21147/j.issn.1000-9604.2023.03.09
Abstract:
ObjectivePTPRD and PTPRT are phosphatases of the JAK-STAT pathway related to immunotherapy. However, the role and mechanism of PTPRD and PTPRT mutations in multiple cancers remains unclear. MethodsClinical data and PTPRD/PTPRT mutation information from 12 cohorts were collected and classified as a discovery cohort and three validation cohorts. The association between PTPRD/PTPRT mutations and immunotherapeutic efficacy was analyzed. Then, the association between PTPRD/PTPRT mutation and immune profiles was analyzed using The Cancer Genome Atlas (TCGA) cohort. ResultsA total of 2,392 patients across 20 cancer types were included in this study. Our results showed that patients harboring PTPRD/PTPRT mutation, especially co-mutations, had a significantly elevated response rate to immunotherapy in multiple cancers. Patients with PTPRD/PTPRT mutation had a higher objective response rate (ORR) (P=0.002), longer overall survival (OS) (P=0.005) and progression-free survival (PFS) (P=0.038). Importantly, the above findings were further verified in validation cohorts. In addition, we found that the PTPRD/PTPRT co-mutations (co-mut) subgroup exhibited an immune-activated phenotype, the wild-type subgroup tended to have an immune-desert phenotype, and the uni-mutation (uni-mut) subgroup might have an immune-mixed phenotype. Our further analyses suggested that combining programmed cell death ligand 1 (PD-L1) expression and PTPRD/PTPRT mutation can be used to screen patients who may benefit from immunotherapy. ConclusionsPTPRD/PTPRT mutation could serve as a potential predictive biomarker for cancer immunotherapy.
