TUMOR MICROENVIRONMENT MAY DRIVE NK CELL EXHAUSTION AND IMPAIRED GLUCOSE UPTAKE THAT LIKELY CONTRIBUTES TO NK CELL SUPPRESSION AND TUMOR PROGRESSION IN HUMAN RENAL CELL CARCINOMA

SECCHIARI, FLORENCIA; NUÑEZ, SOL Y.; ZIBLAT, ANDREA; ROBEGNO, A; RICHARDS, NICOLÁS; REGGE, MARÍA VICTORIA; AMERI, CARLOS; RIOS PITA, H; FRIEDRICH, ADRIÁN; SANTILLI, MARÍA CECILIA; FUERTES, MERCEDES BEATRIZ; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER

Congreso; Reunion anual de la SAI; 2020

SAI

Renal cell carcinoma (RCC) is an aggressive neoplasm, with metastatic potential.Nephrectomy constitutes the gold-standard treatment, and recently, immunecheckpoint inhibitors have been approved for the treatment of advanced RCC. Asthere are no validated molecular targets in RCC, we previously characterized theexpression pattern of ligands of the NK cell activating receptor NKG2D on peripheralblood mononuclear cells (PBMC), tumor infiltrating lymphoid cells (TIL) and tumorcells from RCC patients and observed that tumor cells exhibited high expression ofMICA, while TIL (but not PBMC from RCC patients), exhibited high expression ofMICA, ULBP3 and ULBP4. Additionally, tumor infiltrating NK cells (TINK) and CD8T cells displayed increased expression of NKG2D and TINK exhibited a pronouncedreduced degranulation and IFN-γ production ability compared to PBNK from RCCpatients, which indicates a functional impairment. In this work, and to gain a deeperinsight into these dysfunctional TINK in RCC, we further characterized TINK in termsof Tim-3 expression (exhaustion marker) and glucose uptake (using the fluorescentglucose analog 2-NBDG in the absence or presence of cytokine stimulation) bymulticolor flow cytometry. No differences were observed in the expression of Tim-3between PBNK from RCC patients and HD. However, TINK expressed higheramounts of Tim-3 compared to PBNK from RCC patients. Moreover, compared toPBNK from HD, TINK and PBNK from RCC patients exhibited an impaired glucoseuptake after cytokine stimulation. Although Tim-3 expression and glucose uptake inTINK did not reach statistical significance yet due to the low number of samples sofar analyzed, our preliminary results unravel a likely novel tumor microenvironment-driven suppressive circuit that connects Tim-3 expression, NK cell exhaustion,functional impairment and glucose uptake that drives NK cell into dysfunctional TINKand that likely contribute to tumor progression.