Immunogenic stress and death of cancer cells: Contribution of antigenicity vs adjuvanticity to immunosurveillance

Abstract

Cancer cells are subjected to constant selection by the immune system, meaning that tumors that become clinically manifest have managed to subvert or hide from immunosurveillance. Immune control can be facilitated by induction of autophagy, as well as by polyploidization of cancer cells. While autophagy causes the release of ATP, a chemotactic signal for myeloid cells, polyploidization can trigger endoplasmic reticulum stress with consequent exposure of the "eat-me" signal calreticulin on the cell surface, thereby facilitating the transfer of tumor antigens into dendritic cells. Hence, both autophagy and polyploidization cause the emission of adjuvant signals that ultimately elicit immune control by CD8 T lymphocytes. We investigated the possibility that autophagy and polyploidization might also affect the antigenicity of cancer cells by altering the immunopeptidome. Mass spectrometry led to the identification of peptides that were presented on major histocompatibility complex (MHC) class I molecules in an autophagy-dependent fashion or that were specifically exposed on the surface of polyploid cells, yet lost upon passage of such cells through immunocompetent (but not immunodeficient) mice. However, the preferential recognition of autophagy-competent and polyploid cells by the innate and cellular immune systems did not correlate with the preferential recognition of such peptides in vivo. Moreover, vaccination with such peptides was unable to elicit tumor growth-inhibitory responses in vivo. We conclude that autophagy and polyploidy increase the immunogenicity of cancer cells mostly by affecting their adjuvanticity rather than their antigenicity.

Integrated analysis of the immunological and genetic status in and across cancer types: impact of mutational signatures beyond tumor mutational burden

“…12 To overcome these limitations, several novel and complementary biomarkers are currently under investigation. Additional to negative predictors of response, [13][14][15][16] which might play an increasingly important role in the near future, tumor mutational burden (TMB) approximating neo-antigenicity 17,18 was observed to predict response to various checkpoint agents in different cancer types. 11,19,20 The potential of TMB as biomarker for immune therapy response independent from PD-L1 was demonstrated in phase III non-small cell lung carcinoma (NSCLC) trials including a retrospective analysis of the Checkmate 026 trial and more recent corroborative data obtained from the Checkmate 227 trial.…”

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…The induction of ICD is justified by the idea that immunogenic apoptotic cells are a proper in vitro source of both antigens and adjuvants for efficient ex vivo DC activation and tumor-specific T-cell stimulation [69,91,112]. Along this line, we have recently performed a review of the literature regarding the modulation of ICD-executed DAMPs and its impact on immature and mature DCs [113].…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…87-103 However, TAAs often display limited antigenicity (reflecting the fact that they generally resemble self-antigens that are covered by tolerance). 104-106 Moreover, tumors emerge and evolve as they become able to escape natural immunosurveillance, 107-110 either because the lose expression of potentially antigenic proteins, and/or because they establish an immunosuppressive milieu that enforces local tolerance. 111-116 Thus, besides a few exceptions and despite promising preclinical findings, 117 multiple studies demonstrate that peptide-based vaccines employed as standalone adjuvanted interventions have limited clinical activity (although they generally cause some signs of tumor-targeting immunity).…”