Antigen processing and immune regulation in the response to tumours

Abstract

SummaryThe MHC class I and II antigen processing and presentation pathways display peptides to circulating CD8 + cytotoxic and CD4 + helper T cells respectively to enable pathogens and transformed cells to be identified. Once detected, T cells become activated and either directly kill the infected / transformed cells (CD8 + cytotoxic T lymphocytes) or orchestrate the activation of the adaptive immune response (CD4 + T cells). The immune surveillance of transformed/tumour cells drives alteration of the antigen processing and presentation pathways to evade detection and hence the immune response. Evasion of the immune response is a significant event tumour development and considered one of the hallmarks of cancer. To avoid immune recognition, tumours employ a multitude of strategies with most resulting in a down-regulation of the MHC class I expression at the cell surface, significantly impairing the ability of CD8 + cytotoxic T lymphocytes to recognize the tumour. Alteration of the expression of key players in antigen processing not only affects MHC class I expression but also significantly alters the repertoire of peptides being presented. These modified peptide repertoires may serve to further reduce the presentation of tumour-specific/associated antigenic epitopes to aid immune evasion and tumour progression. Here we review the modifications to the antigen processing and presentation pathway in tumours and how it affects the anti-tumour immune response, considering the role of tumour-infiltrating cell populations and highlighting possible future therapeutic targets.

Role of the immunosuppressive microenvironment in immunotherapy

“…Accordingly, expression of immune checkpoint–related molecules by both tumor and stromal cells has been reviewed extensively elsewhere 37 Table 1Mechanisms of immunosuppression in the tumor microenvironmentMediatorMechanism of immunosuppressionReferencesCell surface proteins Programmed death-ligand 1Induce T-cell tolerance/anergy after ligation with programmed cell death protein 1 on T cells37 CTLA-4Inhibit activation of naïve T cells37Enhance regulatory T cell function74 ↓Major histocompatibility complex IAvoid detection by effector CD8 T cells75 ↓FASAvoid FAS ligand–mediated cell killing ↓TRAILAvoid TRAIL-mediated cell killing CD39/CD73Convert extracellular immunostimulatory adenosine triphosphate to immunosuppressive adenosine76Secreted cytokines Transforming growth factor betaInhibit T cell priming and infiltration77Suppress effector cell cytotoxicity47 Vascular endothelial growth factorInhibit dendritic cell maturation78Enhance programmed cell death protein 1/programmed death-ligand 1/2 expression79Enhance interleukin-10 secretion Interleukin-10Inhibit major histocompatibility complex II expression on antigen presenting cells80Suppress M1 cytokine secretion81Suppress iNOS (inducible Nitric Oxide Synthase)82Induce T cell anergy83Metabolic pathways Indoleamine-2,3 dioxygenaseConvert tryptophan to kynurenine55Inhibit T cell proliferation84 AdenosineInhibit T cell proliferation and activation85, 86 HypoxiaInhibit effector T cell function87...…”

MAIT cell-mediated cytotoxicity: Roles in host defense and therapeutic potentials in infectious diseases and cancer

“…Being potent and prompt producers of IFN‐γ, activated MAIT cells may indirectly contribute to resolution of certain infections or even eradication of spontaneously arising neoplastic cells. IFN‐γ promotes MHC class I and Fas (CD95) expression on target cells, which could facilitate their detection by CD8 + cytotoxic T lymphocytes and their FasL‐mediated clearance, respectively . Furthermore, MAIT cell‐derived IFN‐γ likely instigates the activation of other effector cell types such as NK cells and MΦs.…”

Tools to define the melanoma‐associated immunopeptidome

“…Evolution of tumours under immune pressure and immune editing has been determined as a key element of immune evasion and subsequent tumour progression . The tumour‐related immunopeptidome is also affected by such immune editing and characteristics of peptide ligands suitable for effective tumour rejection may depend on a number of factors, such as relevance of the source protein for cell survival, dependence of peptide presentation on the antigen presentation machinery and affinity of the peptide towards MHC . Otherwise, target recognition is highly dependent on the relevant T‐cell population and higher‐affinity TCR towards MHC–peptide may be more effective in tumour cell rejection.…”

“…24 The tumour-related immunopeptidome is also affected by such immune editing 25,26 and characteristics of peptide ligands suitable for effective tumour rejection may depend on a number of factors, such as relevance of the source protein for cell survival, dependence of peptide presentation on the antigen presentation machinery and affinity of the peptide towards MHC. 27 Otherwise, target recognition is highly dependent on the relevant T-cell population and higher-affinity TCR towards MHC-peptide may be more effective in tumour cell rejection. Such TCR are generally observed against non-self antigens or in the context of a non-educated Tcell repertoire or mismatched MHC environment.…”