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Mechanisms of Resistance to Immune Checkpoint Blockade

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Abstract

The recent development of effective immune checkpoint inhibition (ICI), first demonstrated in melanoma, has revolutionized cancer treatment. Monoclonal antibodies blocking the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 receptor (PD-1) have shown substantial clinical benefit in a subset of patients across tumor types and in both the metastatic and adjuvant settings. In this article, we review the interaction between the immune system and solid tumors, and describe modes of immune response failure and the physiologic role of immune checkpoints. We also review the known mechanisms of immune checkpoint inhibitors, focusing on US FDA-approved agents targeting CTLA-4 and PD-1. Within this framework, we classify hypothesized tumor intrinsic and extrinsic predictive markers for response and resistance to ICI, and map them to their putative underlying biological mechanism. Finally, we outline future directions in ICI, including the development of new therapeutic targets, rational combination therapies, integrated predictive models for individual patients to optimize therapy, and expansion into different disease types.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, Yawkey 7E, Boston, MA, 02114, USA

    David Liu, Russell W. Jenkins & Ryan J. Sullivan

  2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    David Liu & Russell W. Jenkins

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  1. David Liu
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  2. Russell W. Jenkins
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Correspondence to Ryan J. Sullivan.

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Funding

The authors acknowledge support from the Damon Runyon Cancer Foundation Physician Scientist Training Grant (DL), ASCO Young Investigator Award (DL, RWJ), and Society for Immunotherapy of Cancer—Bristol-Meyers Squibb Postdoctoral Cancer Immunotherapy Translational Fellowship (DL), National Cancer Institute (Grant no. U54 CA224086) (RJS).

Conflict of interest

David Liu declares he has no conflicts of interest that might be relevant to the content of this manuscript. Russell W. Jenkins has ownership interest in pending US Patent Application No. 15/540,346. Ryan J. Sullivan declares institutional funding from BMS, Merck, Novartis, Amgen, Immunocore, BiomedValley Discoveries, Lilly, Pfizer, Viralytics, Adaptimmune, Takeda, Tesaro, Genentech, Array Biopharma, Astex, Alglea, Asana, Sanofi, Infinity, Syndax, and Moderna; advisory board/consulting from Merck, Amgen, Array Biopharma, Syndax, Compugen, Genentech, and Novartis; and research funding from Amgen and Merck.

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Liu, D., Jenkins, R.W. & Sullivan, R.J. Mechanisms of Resistance to Immune Checkpoint Blockade. Am J Clin Dermatol 20, 41–54 (2019). https://doi.org/10.1007/s40257-018-0389-y

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