Epigenetic Modifications and Their Impact on Cancer Immunotherapy

Cancer immunotherapy has revolutionized cancer treatment by harnessing the immune system to fight tumors. However, some patients show limited response, necessitating exploration of new therapeutic approaches. Epigenetic modifications, alterations in gene expression without DNA sequence changes, have emerged as a promising area for overcoming these limitations. This article explores how epigenetic modifications influence cancer immunotherapy and their potential to improve patient outcomes.

Epigenetic in Cancer and Immunotherapy

Cancer cells have a disrupted epigenome, characterized by abnormal DNA methylation patterns and histone modifications. These modifications silence genes that suppress tumors and activate oncogenes, promoting tumor growth and immune evasion. Additionally, the tumor microenvironment (TME), the surrounding cellular environment, is often immunosuppressive. Epigenetic alterations within immune cells like T lymphocytes in the TME can further suppress the immune system's attack on tumors.

Epigenetic regulation of immune cells in the tumor microenvironment. Decreased KLF4 and increased SATB1 expression affect IL-6 (upregulation) and Galectin (downregulation) expression, remodeling anti-tumor DCs into pro-tumor DCs. MDSCs expansion, accumulation and recruitment are favored by STAT3-induced expression of immunosuppressive factors S100A8, Arg1 and S100A9. In this cell population, STAT3 expression is controlled by DNMTT3a/b, HDAC6 and HDAC11. Macrophages can convert into TAMs under the influence of multiple epigenetic factors, including DNMT3b, PRMT1, HDAC3/4, HDAC9 and SIRT2, favoring acquisition of the M2 phenotype through various pathways, such as increased PPARγ and Arg1 expression as well as downregulation of inflammatory factors TNF-α and IL-1β. SMYD3 activates M2 marker ALOX15. Impaired NK-cell anti-tumor cytotoxicity can be the result of increased EZH2 expression, which downregulates activating NK-cell receptor NKG2D through enhanced H3K27me3 levels. The same way, EZH2 also regulates inhibition of regulatory T-cell pro-inflammatory activities. Naïve CD8 + T-cells differentiate into TILs or exhausted CD8 + cells dependent on epigenetic profile. Whereas specific DNA methylation patterns of CTLA4, PDCD1 and LAG3 are identified in exhausted CD8 + T-cells, DNMT1 and EZH2 inhibit CD8 + TILs infiltration through downregulation of CXCL9 and CXCL10 chemokines. TGF-β and SATB1 affect TILs infiltration by controlling PD-1 expression. DCs, dendritic cells; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages; NK, natural killer; Tregs, regulatory T-cells; TILs, tumor-infiltrating lymphocytes

Targeting Epigenetic Mechanisms to Enhance Immunotherapy

Two main drug classes target epigenetic modifications: DNA methyltransferase inhibitors (DNMTis) and histone deacetylase inhibitors (HDACis). DNMTis reverse DNA methylation, potentially reactivating silenced tumor suppressor genes and making tumors more susceptible to immune attack. HDACis modify histone acetylation patterns, promoting the expression of genes involved in antigen presentation and T cell activation, thereby stimulating the anti-tumor immune response. Researchers worldwide are actively investigating these drugs. Companies like Maxanim provide essential reagents, such as enzymes and antibodies, to support this critical research effort.

Epigenetic mechanisms. Epigenetic mechanisms comprise (A) histone posttranslational modifications (HPTMs), (B) DNA methylation, and (C) microRNAs (miRNAs) regulation. Gene expression can be regulated before transcription initiation by HPTMs and DNA methylation. Both mechanisms induce a remodeling of the chromatin structure, thereby making genes either less or more accessible for transcription factors, according to the different epigenetic modifications. Unlike DNA methylation and HPTMs, miRNAs regulate the expression of genes at the post-transcriptional level. miRNAs negatively regulate genes through complementing their mRNAs, which results in mRNA degradation or translational repression.

Combination Strategies: Improving Immunotherapy Efficacy

Combining epigenetic drugs with established immunotherapies, such as immune checkpoint inhibitors (ICIs), shows significant promise. ICIs block immunosuppressive pathways, but their effectiveness can be limited by an immunosuppressive TME. Epigenetic drugs can reprogram the TME, making tumor cells more vulnerable to T cell attack and strengthening the efficacy of ICIs.

Combination strategies to enhance the therapeutic efficacy of PD-1/PD-L1 blockade. A Combination therapy with PD-1 and CTLA-4 blockers. The activation of PD-1/PD-L1 and CTLA-4 can be blocked by anti-PD-1/PD-L1 and CTLA-4 antibodies, respectively. The combined application of PD-1 and CTLA-4 inhibitors produces synergistic effects. B Combination therapy with chemotherapy. Chemotherapy is able to induce ICD, promote the release of tumor antigens and DAMPs, activate DCs, induce local production of CXCL10, recruit T cells to the tumor bed and enhance the differentiation of antitumor-specific CTLs. Chemotherapy can also reduce the number of immunosuppressive cells, such as MDSCs and Tregs. However, systemic chemotherapy shows undifferentiated toxicity to tumor cells and the anticancer immune system, while local chemotherapy enhances immunotherapy by remodeling the TME and attracting activated immune cells to the tumor region. C Combination therapy with radiotherapy. Radiotherapy markedly upregulates the cell adhesion factors ICAM-1 and VCAM-1 on the surface of cancer cells. One of the mechanisms by which radiotherapy may enhance immunotherapy is through activation of certain types of club cells which release proteins that are beneficial to immunotherapy. D Combination therapy with an AMPK activator. Reduced PD-L1 levels in the presence of AMPK activation could enhance the efficacy of combining ICB with an AMPK activator. E Combination therapy with STING agonists. The cGAS-STING pathway is essential for linking the innate immunity and adaptive immunity against cancers. Cancer cells can escape immune surveillance by inactivating the cGAS-STING pathway. Therefore, ICB can be combined with STING agonists to boost the efficacy of immunotherapy. F “Cold” tumors lack activated tumor-specific T cells, which may contribute to primary resistance to ICBs. Effective combination therapy can turn these tumors into hot tumors that are sensitive to ICBs

Challenges and Future Directions

Despite promising pre-clinical and clinical data, challenges remain. Identifying the most effective epigenetic targets and tailoring therapies to specific tumor types and patient groups require further investigation. Additionally, understanding the complex interaction between epigenetic modifications and other aspects of the immune response is crucial for maximizing therapeutic benefit while minimizing side effects.

Conclusion

Epigenetic modifications play a critical role in both tumor development and immune evasion. Targeting these modifications with epigenetic drugs offers a powerful approach to enhance the effectiveness of cancer immunotherapy. Continued research holds the potential to refine combination strategies and personalize epigenetic therapies for improved patient outcomes.

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Epigenetic Modifications and Their Impact on Cancer Immunotherapy
Gen store June 20, 2024
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