UPREGULATION OF THE EXHAUSTION-ASSOCIATED RECEPTOR TIM-3 ON NK CELLS REQUIRES THE COOPERATION BETWEEN TUMOR AND ACCESSORY CELLS

MARÍA SOFÍA AMARILLA; ALDANA TROTTA; MARÍA NATALIA RUBINSZTAIN; BELÉN CANDELA LOZADA MONTANARI; ADRIÁN DAVID FRIEDRICH; MARÍA VICTORIA REGGE; MARÍA CECILIA SANTILLI; MARIANA GANTOV; CAROLINA INÉS DOMAICA; FUERTES MERCEDES BEATRIZ; ZWIRNER NORBERTO WALTER

Congreso; Reunion anual de la SAI; 2023

Immune checkpoint inhibitors have revolutionized immuno-oncology (IO). Recently,natural killer (NK) cells have been positioned at the forefront of IO strategies. However,within the tumor microenvironment (TME), NK usually develop an exhausted phenotype,characterized by an upregulation of NK cell inhibitory checkpoints (NKCIC). For instance,we observed that TIM-3 is upregulated on tumor-infiltrating NK cells from patients withclear cell renal cell carcinoma (ccRCC). Although the blockage of some of these NKCICresults in a reinvigoration of their effector functions, the actual stimuli and mechanismsthat induce the expression of NKCIC remain poorly defined. Accordingly, our aim was to elucidate the stimuli that trigger the increased expression of several NKCIC such as TIM-3, LAG-3, TIGIT, PVRIG and PD-1. When NK cells isolated from healthy donors (HD) were stimulated with optimal doses of IL-15, a cytokine that promotes NK cell survivaland proliferation, for short (2 d) or long (14 d) periods, we did not observe appreciablechanges in the frequency of NK cells (CD3-CD56+) expressing NKCIC, evaluated by flowcytometry. We also didn ́t observe appreciable changes when isolated NK cells from HDwere cultured with an ccRCC cell line (786-O) for 2 d or 5 d. However, when peripheralblood mononuclear cells (PBMC) from HD were cultured with 786-O cells for 2 d, asignificant increase in the frequency of TIM-3+ NK cells was observed (Mean ± SD, NK:19,0 ± 17,4 vs NK+786-O: 53,3 ±14,3, p