Tumor-infiltrating CD8+ PD-1 high T lymphocytes from breast cancer patients exhibit a phenotype associated to terminal exhaustion

ABRATE CAROLINA; VALENTINA BRUNOTTO; BOSSIO SABRINA; BOCCARDO SANTIAGO; BORCOMAN EDITH; GRUPPI ADRIANA; ACOSTA RODRIGUEZ EVA; ELIANE PIAGGIO; MONTES CAROLINA

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencias 2022 SAIC ? SAI&FAIC ? SAFIS; 2022

SAIC ? SAI&FAIC ? SAFIS

The focus in cancer immunotherapy has been mainly posed in CD8+ T lymphocytes. Evidences suggest that CD8+ T cell subsets characterized by distinct expression levels of PD-1 diverge in their state of exhaustion and potential for reinvigoration by PD-1 blockade. In this work, we aim to perform a comprehensive study of PD-1hiCD8+ and CD8+PD-1low T cells in untreated breast cancer (BC) patients. We included in our study different BC subtypes according the expression of estrogen, progesterone or HER2 receptors. We studied the presence and phenotype of the PD-1 expressing CD8+ T cell subpopulations in tumor, juxta-tumor (JT), invaded and non-invaded tumor-draining lymph node (I-dLN and NI-dLN). By flow cytometry we evaluated the expression of inhibitor receptors (PD-1, TIGIT), proliferation, activation, and exhaustion markers (Ki-67, OX40 and CD39) and cytokine production on CD8+ T cells. We observed higher % of CD8+PD-1high cells in Tumor than JT, I-dLN and NI-dLN (p<0.01, p<0.001 and p<0.0001 respectively). The frequency of CD8+PD-1low cells was higher in tumor compared to I-dLN and NI-dLN (p<0.0001 for all). The evaluation of CD39, OX40 and Ki67 revealed that CD8+PD-1high cells exhibited higher frequencies of these molecules than CD8+PD-1low cells in the tissues evaluated (p<0.05 for all). Accordingly, CD8+PD-1high cells from tumors, JT and d-ILN showed higher % of TIGIT+ cells respect to PD-1low counterpart (p<0.01 for all). We observed that compared to CD8+PD-1low T cells, CD8+PD-1high T cells from tumors and I-dLN exhibited an impairment of TNF and INF production. Our results suggest that, PD-1 expression level identifies T lymphocytes with distinct phenotype. CD8+PD-1high T cells from tumors, JT and I-dLN exhibit a phenotype associated to terminal exhaustion. The characterization of a distinct state of PD-1 expressing CD8+ T lymphocytes from BC patients provide novel potential avenues for therapeutic intervention.