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Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by Anticancer Therapies in the Era of Checkpoint InhibitorsA Review

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Importance  Although typically impressive, objective responses to immune checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced cancer. The majority of patients do not respond due to cell-intrinsic resistance mechanisms, including human leukocyte antigen (HLA) class I antigen-processing machinery (APM) defects. The APM defects, which have a negative effect on neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the majority of malignant tumors. These defects are caused by gene variations in less than 25% of cases and by dysregulated signaling and/or epigenetic changes in most of the remaining cases, making them frequently correctable. This narrative review summarizes the growing clinical evidence that chemotherapy, targeted therapies, and, to a lesser extent, radiotherapy can correct HLA class I APM defects in cancer cells and improve responses to ICIs.

Observations  Most chemotherapeutics enhance HLA class I APM component expression and function in cancer cells, tumor CTL infiltration, and responses to ICIs in preclinical and clinical models. Despite preclinical evidence, radiotherapy does not appear to upregulate HLA class I expression in patients and does not enhance the efficacy of ICIs in clinical settings. The latter findings underscore the need to optimize the dose and schedule of radiation and timing of ICI administration to maximize their immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and EZH2 inhibitors) enhance HLA class I APM component expression and function in many cancer types, a crucial contributor to their synergy with ICIs in patients. Furthermore, epidermal growth factor receptor (EGFR) inhibitors and BRAF/mitogen-activated protein kinase kinase inhibitors are effective at upregulating HLA class I expression in EGFR- and BRAF-variant tumors, respectively; these changes may contribute to the clinical responses induced by these inhibitors in combination with ICIs.

Conclusions and Relevance  This narrative review summarizes evidence indicating that chemotherapy and targeted therapies are effective at enhancing HLA class I APM component expression and function in cancer cells. The resulting increased immunogenicity and recognition and elimination of cancer cells by cognate CTLs contributes to the antitumor activity of these therapies as well as to their synergy with ICIs.

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Article Information

Accepted for Publication: June 16, 2021.

Published Online: December 23, 2021. doi:10.1001/jamaoncol.2021.5970

Corresponding Author: Soldano Ferrone, MD, PhD, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Jackson 9, Boston, MA 02114 (sferrone@mgh.harvard.edu).

Author Contributions: Dr Ferrone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Sadagopan, Michelakos, Boyiadzis, S. Ferrone.

Drafting of the manuscript: Sadagopan, Boyiadzis, S. Ferrone.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Michelakos, Boyiadzis, S. Ferrone.

Supervision: Boyiadzis, C. Ferrone, S. Ferrone.

Conflict of Interest Disclosures: Dr S. Ferrone reported receiving research grants from Merck during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was supported by grants R01DE028172, R01CA230275, R03CA219603, and R03CA253319 from the National Institutes of Health (Drs S. Ferrone and C. Ferrone) and grant W81XWH-20-1-0315 from the Department of Defense (Dr S. Ferrone).

Role of the Funder/Sponsor: The funding institutions had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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