Epigenetic mechanisms of liver tumor resistance to immunotherapy.
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ABSTRACT:
SUBMITTER: Sanceau J
PROVIDER: S-EPMC8473495 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumor immunotherapy inhibits the proliferation and invasion of tumor cells by inducing or enhancing anti-tumor immune responses in active or passive ways. It is the fourth therapeutic method with efficiency and safety in addition to surgery, radiotherapy and chemotherapy. At present, anti-tumor immune related clinical trials have made promising achievements in prolonging progression free survival and overall survival, therefore, FDA approved a variety of immune checkpoint blockers (ICBs) such as nivolumab, pembrolizumab, ipilimumab. However, primary or acquired resistance results in massive perplexity to oncologist and patients. In order to bring further clinical benefit to tumor patients, study on mechanisms of immunotherapy resistance is extremely urgent. This review summarizes related mechanisms of tumor immunotherapy resistance, including MITF suppression, Ezh2 upregulation, TIM-3 upregulation, microRNA-driven deregulation of cytokine expression and et al. Genetic mutations such as PTEN loss, JAK1/2 loss-of-function mutations and Cbl-b deficiency are also involved. Moreover, we have discussed feasible countermeasures, for instance, combining ICBs with PRRs agonists, ARNAX, CpG oligonucleotide, oncolytic peptide LTX-315 and indoleamine 2, 3-dioxygenase inhibitors, respectively. Other methods include combined ICBs with radiotherapy, combined ICBs with blockade of PI3K-AKT, TIM-3 pathway; blockade of Fcγ receptors before anti-PD-1 monoclonal antibodies administration and modulation of the gut microbiome, et al. Mechanisms and countermeasures of immunotherapy resistance still requires further exploration, in expectation to provide novel ideals and basis for tolerant patients.
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Project description:Background: The recent clinical success of immunotherapy represents a turning point in cancer management. But the response rate of immunotherapy is still limited. The inflamed tumor microenvironment has been reported to correlate with response in tumor patients. However, due to the lack of appropriate experimental methods, the reason why the immunotherapeutic resistance still existed on the inflamed tumor microenvironment remains unclear. Materials and Methods: Here, based on single-cell RNA sequencing, we classified the tumor microenvironment into inflamed immunotherapeutic responsive and inflamed non-responsive. Then, phenotype-specific genes were identified to show mechanistic differences between distant microenvironment phenotypes. Finally, we screened for some potential drugs that can convert an unfavorable microenvironment phenotype to a favorable one to aid current immunotherapy. Results: Multiple signaling pathways were phenotypes-specific dysregulated. Compared to non-inflamed microenvironment, the expression of interleukin signaling pathways-associated genes was upregulated in inflamed microenvironment. Compared to inflamed responsive microenvironment, the PPAR signaling pathway-related genes and multiple epigenetic pathways-related genes were, respectively, suppressed and upregulated in the inflamed non-responsive microenvironment, suggesting a potential mechanism of immunotherapeutic resistance. Interestingly, some of the identified phenotype-specific gene signatures have shown their potential to enhance the efficacy of current immunotherapy. Conclusion: These results may contribute to the mechanistic understanding of immunotherapeutic resistance and guide rational therapeutic combinations of distant targeted chemotherapy agents with immunotherapy.
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Project description:BackgroundEpigenetic alterations are known contributors to cancer development and aggressiveness. Additional to alterations in cancer cells, aberrant epigenetic marks are present in cells of the tumor microenvironment, including lymphocytes and tumor-associated macrophages, which are often overlooked but known to be a contributing factor to a favorable environment for tumor growth. Therefore, the main aim of this review is to give an overview of the epigenetic alterations affecting immune cells in the tumor microenvironment to provoke an immunosuppressive function and contribute to cancer development. Moreover, immunotherapy is briefly discussed in the context of epigenetics, describing both its combination with epigenetic drugs and the need for epigenetic biomarkers to predict response to immune checkpoint blockage.Main bodyCombining both topics, epigenetic machinery plays a central role in generating an immunosuppressive environment for cancer growth, which creates a barrier for immunotherapy to be successful. Furthermore, epigenetic-directed compounds may not only affect cancer cells but also immune cells in the tumor microenvironment, which could be beneficial for the clinical response to immunotherapy.ConclusionThus, modulating epigenetics in combination with immunotherapy might be a promising therapeutic option to improve the success of this therapy. Further studies are necessary to (1) understand in depth the impact of the epigenetic machinery in the tumor microenvironment; (2) how the epigenetic machinery can be modulated according to tumor type to increase response to immunotherapy and (3) find reliable biomarkers for a better selection of patients eligible to immunotherapy.
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