ReviewExposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance
Section snippets
Therapeutic targeting of the cancer epigenome
The initiation and progression of cancer is under the control of complex processes governed not only by mutations in tumor suppressor genes and oncogenes but also by processes leading to epigenetic dysregulation. The field of epigenetics focuses on the heritable changes governing gene expression which do not depend upon on changes to primary DNA sequences. These changes to the epigenetic landscape are modulated predominantly by DNA methylation and post translational changes to histones,
MHC antigen processing and presenting machinery and immune escape
Immune system responses are governed by the interplay between the innate and adaptive immune system and through selection pressure, cancers which grow and spread acquire and maintain adaptations which enable them to survive despite immune surveillance. Cancer epitopes should be recognized as foreign by antigen presenting cells, which are capable of taking up exogenous antigens, becoming activated and presenting cancer-associated antigens to T cells leading to T cell priming and adaptive immune
Increasing immune trafficking to the tumor microenvironment
Multiple studies have shown that responses to immunotherapy are more likely in the setting of a brisk T cell infiltrate or in the presence of surrounding tertiary lymphoid structures. Therefore a common mechanism of immune evasion exploited by tumor cells is keeping lymphocytes, particularly cytotoxic T cells (CTLs), from trafficking into the tumor microenvironment [66]. This is mediated by the release of immunosuppressive cytokines and chemokines from tumor cells which support their growth and
New directions and limitations
Current trends in the treatment of cancer are moving towards choosing appropriate therapies based upon biomarker-driven precision medicine approaches to patient care. This will enable patients to have not only appropriate therapies delivered in a biologically rationale manner, but also administered in the appropriate sequence in order to maximize responses. The field of biomarker research will also need to expand to define not only which mutations a cancer possesses, but more importantly, to
Acknowledgement
Kelly Olino, MD was funded by the K12 Calabresi Immuno-Oncology Training Program; Tristen Park, MD was funded by the K12 Calabresi Immune-Oncology Training Program and the Lionheart Cancer Foundation.
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2023, Biomedicine and PharmacotherapyCombination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy
2023, International ImmunopharmacologyAdvances in immunotherapy for MMR proficient colorectal cancer
2022, Cancer Treatment ReviewsCitation Excerpt :MMRp mCRCs that responded to the EGFR antibody cetuximab showed subtype switches from CMS2 to CMS2, increase T-cell inflammation and upregulation of a pan-cancer immunotherapy response signature and of PD-L1 and LAG3 immune checkpoints, suggesting that specific therapies potentially overcome the immune-excluded phenotype[32]. Other epigenetic approaches are being developed although none has displayed clinical benefit yet [109]. A large number of immunotherapy trials in MMRp CRC are currently underway and a selection showing the range of strategies pursued are presented in Table 2.
Molecular subtyping of small cell lung cancer
2022, Seminars in Cancer BiologyCitation Excerpt :The advent of immune checkpoint inhibitors is a breakthrough in immunotherapy for tumors. Immune checkpoint inhibitors, represented by CTLA-4 inhibitors and PD-1/PD-L1 inhibitors, have been effective in the treatment of several malignancies [70–72]. The primary immune checkpoint inhibitors for SCLC are atelizumab and durvalumab [73–75].
Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer
2022, Seminars in Cancer BiologyCitation Excerpt :Cancer resistance to immunotherapy is driven by extrinsic factors (immunosuppressive cell populations, etc.) and tumor cell intrinsic factors (genetic and epigenetic mechanisms, etc.) that lead to immune escape [106]. Epigenetic therapy stimulates antitumor immunity both in immune cells and tumor cells, and thus overcomes some of the limitations of current immunotherapy [14,107]. Thus, it is of importance to develop and apply combination therapies that include epigenetic inhibitors and immunotherapy in SCLC.
Immune checkpoint inhibitors in HCC: Cellular, molecular and systemic data
2022, Seminars in Cancer BiologyCitation Excerpt :A phase Ib clinical trial is currently underway to assess the safety, tolerability, and pharmacokinetics of OMP-54F28 (a Wnt inhibitor) when combined with sorafenib in HCC (Table 6). Evidence has implicated chromatin remodelling in the creation of an immunosuppressive environment and resistance to ICIs through affecting antigen processing and presentation, immune trafficking, PDL1 expression and immune cell exhaustion status [204]. Thus, epigenetic therapies may enhance immunotherapy in HCC.