Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

Abstract

SummaryAntigen cross‐priming of CD8+ T cells is a critical process necessary for the effective expansion and activation of CD8+ T cells endowed with the ability to recognize and destroy tumor cells. The cross‐presentation of tumor antigens to cross‐prime CD8+ T cells is mainly mediated, if not only, by a subset of professional antigen‐presenting cells termed type‐1 conventional dendritic cells (cDC1). The demise of malignant cells can be immunogenic if it occurs in the context of premortem stress. These ways of dying are termed immunogenic cell death (ICD) and are associated with biochemical features favoring cDC1 for the efficient cross‐priming of tumor antigens. Immunosurveillance and the success of immunotherapies heavily rely on the ability of cytotoxic immune cells, primarily CD8+ T cells and NK cells, to detect and eliminate tumor cells through mechanisms collectively known as cytotoxicity. Recent studies have revealed the significance of NK‐ and CTL‐mediated cytotoxicity as a prominent form of immunogenic cell death, resulting in mechanisms that promote and sustain antigen‐specific immune responses. This review focuses on the mechanisms underlying the cross‐presentation of antigens released during tumor cell killing by cytotoxic immune cells, with an emphasis on the role of cDC1 cells. Indeed, cDC1s are instrumental in the effectiveness of most immunotherapies, underscoring the significance of tumor antigen cross‐priming in contexts of immunogenic cell death. The notion of the potent immunogenicity of cell death resulting from NK or cytotoxic T lymphocyte (CTL)‐mediated cytotoxicity has far‐reaching implications for cancer immunotherapy.

Merkel Cell Carcinoma: Integrating Epidemiology, Immunology, and Therapeutic Updates

“…They are equipped to efficiently uptake antigen from dying cells, deliver cell-associated antigen to early endosomes, and owing to lower proteolysis show increased antigen retention [ 25 ]. Captured antigen is processed into small fragments, loaded onto MHC class I molecules, transported to the cell surface where this peptide/MHC class I complexes are presented to CD8+ T cells [ 26 ]. Those CD8 T cells, which encounter their cognate antigen presented by a cDC1 will be activated, and in the presence of additional costimulatory signals will undergo clonal expansion to form the population of antigen-specific CTLs able to recognize and eliminate cells expressing the same antigen [ 27 , 28 ].…”

Mechanisms of programmed cell death

“…Importantly, this process of T-cell-mediated cytotoxicity can elicit immunogenic cell death, hence amplifying the phenomenon and protracting the anticancer immune response. 19 However, cell death affecting immune cells may play down such a desirable immunosurveillance. Specifically, it appears that dying neutrophil granulocytes produce so-called neutrophil extracellular traps (NETs) that shield cancer cells from cytotoxic immunity, hence impairing their clearance.…”

“…Such dendritic cells educate cytotoxic T lymphocytes to recognize and lyse malignant cells. Importantly, this process of T‐cell‐mediated cytotoxicity can elicit immunogenic cell death, hence amplifying the phenomenon and protracting the anticancer immune response 19 . However, cell death affecting immune cells may play down such a desirable immunosurveillance.…”