Elsevier

Seminars in Cancer Biology

Volume 65, October 2020, Pages 114-122
Seminars in Cancer Biology

Review
Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance

https://doi.org/10.1016/j.semcancer.2020.01.001Get rights and content

Abstract

Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1–4 merkel cell carcinoma5, urological cancers6–8, non-small cell lung cancer9–11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.

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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