MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy.

Annelisa M Cornel,Stefan Nierkens,Iris L Mimpen

doi:10.3390/cancers12071760

Abstract

In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8+ T-cells. Downregulation of MHC-I has been described in 40–90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer.

Highlights

In recent years, major advances have been made in cancer immunotherapy, thereby drastically improving the prognosis of cancer patients
Several types of Food and Drug Administration (FDA)-approved immunotherapies, such as checkpoint inhibitors (CPI), chimeric antigen receptor (CAR) T-cells, and dendritic cell vaccines, aim to boost T-cell-mediated cytotoxicity to combat cancer. These treatments led to increased survival chances, for patients suffering from hematological cancers, but translation to the solid tumor setting was found difficult
This review aims to provide an overview of the mechanisms underlying reversible major histocompatibility complex class I (MHC-I) downregulation and demonstrate potential therapeutic targets to induce major histocompatibility complex (MHC)-I expression and improve T-cell-mediated cytotoxicity in cancer

Summary

Introduction

Major advances have been made in cancer immunotherapy, thereby drastically improving the prognosis of cancer patients. Several types of Food and Drug Administration (FDA)-approved immunotherapies, such as checkpoint inhibitors (CPI), chimeric antigen receptor (CAR) T-cells, and dendritic cell vaccines, aim to boost T-cell-mediated cytotoxicity to combat cancer. These treatments led to increased survival chances, for patients suffering from hematological cancers, but translation to the solid tumor setting was found difficult. T-cell-mediated cytotoxicity, is the downregulation of surface display of major histocompatibility complex (MHC) class I, a crucial factor in the initiation of an adaptive immune response. The importance of MHC-I downregulation in immune evasion is substantiated by the observed correlations between

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