The Role of Antigen Processing and Presentation in Cancer and the Efficacy of Immune Checkpoint Inhibitor Immunotherapy

Abstract

Recent clinical successes of cancer immunotherapy using immune checkpoint inhibitors (ICIs) are rapidly changing the landscape of cancer treatment. Regardless of initial impressive clinical results though, the therapeutic benefit of ICIs appears to be limited to a subset of patients and tumor types. Recent analyses have revealed that the potency of ICI therapies depends on the efficient presentation of tumor-specific antigens by cancer cells and professional antigen presenting cells. Here, we review current knowledge on the role of antigen presentation in cancer. We focus on intracellular antigen processing and presentation by Major Histocompatibility class I (MHCI) molecules and how it can affect cancer immune evasion. Finally, we discuss the pharmacological tractability of manipulating intracellular antigen processing as a complementary approach to enhance tumor immunogenicity and the effectiveness of ICI immunotherapy.

Keywords: adaptive immunity; aminopeptidase; antigen presentation; antigen processing; antigenic peptide; cancer; human leukocyte antigens; immune checkpoint inhibitor(s); immunotherapy; major histocompatibility complex; neoantigen.

Figure 1

Overview of the Major Histocompatibility Class (MHC) class I pathway of antigen processing and presentation and the alternative pathway of cross-presentation.

Figure 2

Defects in different components of the antigen processing and presentation machinery that can underlie immune evasion by cancer.

Figure 3

Combinatorial strategies under investigation that aim to enhance efficacy of immune checkpoint inhibitor (ICI) immunotherapy (PRC: Polycomb repressive complex).

Figure 4

Schematic representation of antigen processing and presentation in cancer immune evasion and immune re-activation by ICIs and manipulation of intracellular antigen processing. (Panel A) tumor antigens are processed by the proteasome but then destroyed by ER aminopeptidases ERAP1 or ERAP2 resulting in lack of presentation on the cell surface. Overexpression of PD-L1 on the cancer cell surface downregulates cytotoxic T-lymphocyte responses. Synergism between these two mechanisms results in efficient immune evasion by the tumor. (Panel B) Immune-checkpoint inhibitors can help activate T cells but lack of tumor antigen presentation limits cytotoxic responses. (Panel C) inhibition of ERAP1 and ERAP2 can help rescue tumor-associated antigenic peptides from destruction and promote their presentation, which, in combination with ICI treatment, can help re-activate T cell cytotoxic responses against the tumor.