EXHAUSTED T CELLS (TIM-3+PD-1+) INFILTRATE TUMORS OF 4T1 MAMMARY CARCINOMA BEARING MICE.

CANALE F; RAMELLO MC; TOSELLO BOARI J; ARAUJO FURLÁN CL; GOROSITO SERRÁN M; ACOSTA RODRIGUEZ EV; MONTES CL

Congreso; First Argentinean Spring Course in Advance Immunology and LXI Reunión Anual de la Sociedad Argentina de Inmunología.; 2013

T cell exhaustion is a state of T cell dysfunction that arises during chronic infections and cancer. It is defined by poor effector functions, sustained expression of inhibitory receptors like PD-1 and Tim-3 and different transcriptional signatures. We investigated this cell population in blood, tumor, lymph node and lung of 4T1 mammary carcinoma bearing mice. We observed that 29 days post tumor cells injection (pti) higher frequency of CD4+ than CD8+ T-cells (p<0.001) are recruited to tumor. However the frequency of Tim-3+PD-1+(DP) cells is higher within the CD8+population (16.3%±4.3 vs 1.7%±0.5). By flow cytometry we determined that the % of CD4+ and CD8+ DP T cells producing intracellular TNF and IL-2 is reduced respect to CD4+ and CD8+ Tim-3-PD- 1-(DN) (CD4+TNF+p<0.001, CD4+IL-2+p<0.001 ,CD8+TNF+p<0.001, CD8+IL-2+ p<0.001).We did not detected changes in IFNg-producing cells. The % of IL-10 and TGFb-producing cells within the CD4+DP cells was higher than CD4+DN T-cells (IL-10 p<0.001, TGFb p<0.05). CD8+DP cells were present in blood of tumor-bearing mice (11.2%±3.3 vs control mice 0.8%±0.2). In lymph nodes both populations were absent. Lungs of tumor-bearing mice showed low T-cell infiltration; only CD4+PD- 1hi T-cells were detected. Interestingly we observed infiltration of CD11b+Ly6G+ (p<0.001) and Ly6ChiMHCIIlo cells (p<0.01) compared to control mice. On day 34 pti we observed higher % of CD4+ and CD8+DP in tumor. The frequency of IL-2 and TNF producing CD4+ and CD8+ DP cells was reduced but IFNg production remained intact. The frequency of IL-10 producing CD4+ DP T-cells was similar to day 29, while within CD8+ population the main IL-10 producers were DP cells (p<0.05). We detected the same lymphocyte and myeloid cell infiltration in lungs compared to day 29. Overall results demonstrated that tumor-bearing mice exhibit tumor infiltrated lymphocytes with characteristics of exhaustion but capable to produce IL-10, which may have an impact in tumor progression.