Microenvironmental signals shaping NK‐cell reactivity in cancer

Abstract

Since the postulation of the “missing‐self” concept, much progress has been made in defining requirements for NK‐cell activation. Unlike T lymphocytes that process signals from receptors in a hierarchic manner dominated by the T‐cell receptors, NK cells integrate receptor signals more “democratically.” Signals originate not only the downstream of cell‐surface receptors triggered by membrane‐bound ligands or cytokines, but are also mediated by specialized microenvironmental sensors that perceive the cellular surrounding by detecting metabolites or the availability of oxygen. Thus, NK‐cell effector functions are driven in an organ and disease‐dependent manner. Here, we review the latest findings on how NK‐cell reactivity in cancer is determined by the reception and integration of complex signals. Finally, we discuss how this knowledge can be exploited to guide novel combinatorial approaches for NK‐cell‐based anticancer therapies.

CIMT 2023: report on the 20th Annual Meeting of the Association for Cancer Immunotherapy

“…Adelheid Cerwenka (Heidelberg University, Medical Faculty Mannheim, Germany) is focusing on overcoming NK-cell dysfunction in the hostile TME. 42 Using scRNA-seq of NK cells isolated from RMA-S tumors, Cerwenka and her team found that NK cells up-regulate the hypoxia-inducible transcription factor HIF-1α. 43 Analysis of NK-cell functionality after culture in hypoxic conditions revealed reduced effector function, which prompted Cerwenka and her colleagues to investigate the role of HIF-1α in NK cells.…”

Altered NCR3 Splice Variants May Result in Deficient NK Cell Function in Renal Cell Carcinoma Patients

“…Overall, NKp30 + NK cells were enriched in renal carcinoma, but the inhibitory effect due to the altered NCR3 splice variants was predominant, which resulted in a NKp30-mediated NK cell cytotoxicity effect that was also deficient. Impaired NK effector function may be related to the potent immunosuppressive activity of the tumour microenvironment (TME) (36)(37)(38)(39). Such distinct expression of NCR3 splice variants is influenced by the cytokine microenvironment, which is extremely complex in vivo, especially in tumour tissues (40,41).…”