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; SIERRA, JESSICA MARIEL; NÚÑEZ, SOL YANEL; ZIBLAT, ANDREA; AGUSTIN ROVEGNO; RICHARDS, NICOLAS; MARIA VICTORIA REGGE; AMERI, CARLOS; RIOS PITA, HERNANDO; ADRIAN FRIEDRICH; MARIA CECILIA, SANTILLI; FUERTES, MERCEDES BEATRIZ; DOMAICA, CAROLINA INÉS; ZWIRNER, NORBERTO WALTER

CABA

Congreso; REUNIÓN DE SOCIEDADES DE BIOCIENCIAS 2020; 2020

SAI/ SAIC/SAFIS

Renal cell carcinoma (RCC) is an aggressive neoplasm, with metastatic potential. Nephrectomy constitutes the gold-standard treatment, and recently, immune checkpoint inhibitors have been approved for the treatment of advanced RCC. As there are no validated molecular targets in RCC, we previously characterized the expression pattern of ligands of the NK cell activating receptor NKG2D on peripheral blood mononuclear cells (PBMC), tumor infiltrating lymphoid cells (TIL) and tumor cells from RCC patients and observed that tumor cells exhibited high expression of MICA, while TIL (but not PBMC from RCC patients), exhibited high expression of MICA, ULBP3 and ULBP4. Additionally, tumor infiltrating NK cells (TINK) and CD8 T cells displayed increased expression of NKG2D and TINK exhibited a pronounced reduced degranulation and IFN-gamma production ability compared to PBNK from RCC patients, which indicates a functional impairment. In this work, and to gain a deeper insight into these dysfunctional TINK in RCC, we further characterized TINK in terms of Tim-3 expression (exhaustion marker) and glucose uptake (using the fluorescent glucose analog 2-NBDG in the absence or presence of cytokine stimulation) by multicolor flow cytometry. No differences were observed in the expression of Tim-3 between PBNK from RCC patients and HD. However, TINK expressed higher amounts of Tim-3 compared to PBNK from RCC patients. Moreover, compared to PBNK from HD, TINK and PBNK from RCC patients exhibited an impaired glucose uptake after cytokine stimulation. Although Tim-3 expression and glucose uptake in TINK did not reach statistical significance yet due to the low number of samples so far 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 TINK and that likely contribute to tumor progression.