Absence of CD39 may induce a pre-exhausted phenotype on tumor-infiltrating CD8+ T lymphocytes

ABRATE CAROLINA; BOSSIO SABRINA; BOCCARDO SANTIAGO; RODRIGUEZ CONSTANZA; GRUPPI ADRIANA; ACOSTA RODRIGUEZ EVA; MONTES CAROLINA

Congreso; Reunión Conjunta SAIC SAI AAFE NANOMED.AR; 2021

SAIC SAI AAFE NANOMED.AR

We previously demonstrated that CD39KO tumor-bearing mice exhibita higher % of tumor-infiltrating (TI) CD8+ T cells with effectorphenotype as well as a higher % of specific TI-CD8+ T cells thanWild type (WT). CD39 participates in the generation of adenosine,an immunosuppressive molecule that interferes in the anti-tumor response.In this work, we evaluated the role of CD39 on TI-CD8+ Tcells. C57BL/6 WT and CD39KO mice were injected with 1x106B16F10-OVA tumor cells, 17 days after injection, we evaluated byflow cytometry the expression of inhibitor receptors (IRc) (PD-1 andTIM-3), transcription factors (TF) related to exhaustion (TOX, TCF-1,EOMES, T-bet and IRF-4) and cytotoxic related molecules (granzimeB (GzB), perforin, and CD107) on TI-CD8+ T cells. CD39 KOand WT tumor bearing mice exhibited two PD-1 expressing populations:a PD-1high and PD-1low; however, CD39KO mice exhibiteda higher % of PD-1low TI-CD8+ T cells than WT(p<0.005). CD39KOand WT mice showed a high % of PD-1high cells co-expressed TIM-3(82,4±6,1 and 80,3±17,9 respectively), an IRc related to terminalexhaustion, while a low % of PD-1low cells were TIM-3+ (17,5±11,2and 34,0±19,9). PD-1low cells from CD39 and WT mice also exhibitedlower expression of TBET, EOMES, and IRF4 than PD-1high cells(p<0.05). Whereas most PD-1low TI-CD8+ T cells from CD39 KO andWT were TCF1+ (65.4±14.4 and 71.4±11.5), a TF related to pre-exhaustion,PD-1high CD8+ cells were TOX+ and TCF-1- (92.8±4.2 and86.4±7.5). TI-CD8+ T cells cytotoxicity increase as they becomemore exhausted, accordingly, a higher % of CD8+ GzB+, perforin+and CD107+ cells were found within PD-1high cells compared to PD-1low (p<0.05) TI-CD8+ T cells. Our results suggest that the absenceof CD39 may favor a pre-exhausted phenotype on TI-CD8+ T cells,which are known to respond better than terminal exhausted T cellsto anti-checkpoints, reinforcing the idea that CD39 could be consideras a promising target in anti-tumor immunotherapy.CD39, CD8+ T Lymphocyte, Tumor, Exhaustion.