The cell stress and immunity cycle in cancer: Toward next generation of cancer immunotherapy

Abstract

SummaryThe cellular stress and immunity cycle is a cornerstone of organismal homeostasis. Stress activates intracellular and intercellular communications within a tissue or organ to initiate adaptive responses aiming to resolve the origin of this stress. If such local measures are unable to ameliorate this stress, then intercellular communications expand toward immune activation with the aim of recruiting immune cells to effectively resolve the situation while executing tissue repair to ameliorate any damage and facilitate homeostasis. This cellular stress‐immunity cycle is severely dysregulated in diseased contexts like cancer. On one hand, cancer cells dysregulate the normal cellular stress responses to reorient them toward upholding growth at all costs, even at the expense of organismal integrity and homeostasis. On the other hand, the tumors severely dysregulate or inhibit various components of organismal immunity, for example, by facilitating immunosuppressive tumor landscape, lowering antigenicity, and increasing T‐cell dysfunction. In this review we aim to comprehensively discuss the basis behind tumoral dysregulation of cellular stress‐immunity cycle. We also offer insights into current understanding of the regulators and deregulators of this cycle and how they can be targeted for conceptualizing successful cancer immunotherapy regimen.

Mechanisms of programmed cell death

“…If induced in an appropriate fashion, one of the major positive effects of cancer cell stress and death is the induction of immune responses against tumor-associated antigen, thus sensitizing tumors to immunotherapy with immune checkpoint inhibitors. [3][4][5] This has important therapeutic implications because chemotherapeutics that induce immunogenic cell death can be used as first-line treatments to sensitize major cancer types (exemplified by KRAS-mutated colorectal cancer, non-small cell lung cancer and triple-negative breast cancer) to subsequent immunotherapy with antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or PD-1 ligand-1 (PD-L1), as this has been confirmed in several clinical trials.…”

“…Of note, there are multiple different subroutines of cell death, and several if not all of them can be immunogenic, as this has been documented for apoptosis (which involves mitochondrial membrane permeabilization and the activation of caspases 3 and 7) 2,3 but also for necroptosis (with the implication of specific effector molecules including receptor‐interacting kinase 3 (RIP3) and mixed lineage kinase domain‐like pseudokinase (MLKL1)), 6 pyroptosis (involving inflammasome/caspase‐1‐mediated activation of pore‐forming gasdermins), 7 a mixture of pyroptosis, apoptosis, and necroptosis dubbed PANoptosis, 8 ferroptosis (involving lethal membrane damage by peroxidation), 9,10 and cuproptosis (due to copper‐induced aggregation of lipoylated dihydrolipoamide S‐acetyltransferase) 11 . In all cases, cell death can be preceded by immunogenic stress that favors the emission of danger‐associated molecular patterns (DAMPs) appearing on the surface of the cells or secreted into the extracellular space.…”