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

医学 免疫学 癌症研究 细胞毒性T细胞 表观遗传学 抗原 抗原处理 癌症 抗原呈递 人类白细胞抗原 免疫系统 T细胞 生物 内科学 基因 体外 生物化学
作者
Ananthan Sadagopan,Theodoros Michelakos,Gabriella Boyiadzis,Cristina R. Ferrone,Soldano Ferrone
出处
期刊:JAMA Oncology [American Medical Association]
卷期号:8 (3): 462-462 被引量:27
标识
DOI:10.1001/jamaoncol.2021.5970
摘要

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, andEZH2inhibitors) 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 inEGFR- andBRAF-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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