Abstract NG16: Concomitant reduction of PTPN1/PTPN2 activity synergistically enhanced antitumoral effector function of CD8 T cells

CD8 T cells are the main effectors of the adaptive immune system for T helper (Th) 1 or cytotoxic type of responses. In several types of cancer, CD8 lymphocyte infiltrates correlate with good prognosis. CD8 T cells can destroy directly transformed cells and secrete proinflammatory cytokines as IFN-γ and TNF-α, favoring the recruitment and activity of other effectors of antitumoral immunity such as M1 macrophages and NK cells. Hence, in the past few years the potential for the use of adaptive immune system as a base for immunotherapies has expanded enormously and it has focused in CD8 T cells activity. Chimeric antigen receptor (CAR)-T cell technology is one of those striking findings with remarkable successes in the treatment of refractory and/or relapse (r/r) B cell acute lymphoblastic leukemia (B-ALL). The duration of the event-free survival and the rates of overall survival overpass the previously existent treatments prompting to its proposal as therapy for less advanced stages of disease. Previously our laboratory has already shown that modulation of the JAK-STAT inhibitory protein tyrosine phosphatases (PTPs), PTPN1 and PTPN2, enhance proinflammatory type I interferon signaling while decreases the effects of immunosuppressive cytokines acting through STAT3 signaling. Very recently other groups have linked PTPN2 deficiency has with enhanced CD8 antitumoral responses. Unpublished observations from our laboratory using PTPN1/PTPN2 dual specific small molecule inhibitors suggested a role for both phosphatases in the enhancement of CD8 T cell cytotoxic activity. Following this lead, we decided to develop a genetic model to study the contribution of each enzyme to the CD8 T cell ability to respond to antigenic cues. Indeed, we found that a combined total or partial reduction of these genes increased the cytotoxic activity and IFN-γ secretion of CD8 T cells, underscoring synergistic but non-redundant mechanisms of action. The reduced activity of these phosphatases correlated with an increase in the tonic signals mediated by the JAK-STAT axis, particularly STAT 3 and STAT5a. As consequence, cells are sensitized to respond to type 1 and type 2 interferons. Transcriptomic analysis of these enhanced effector cells correlated their functional state with an increased expression, at transcript and protein level, several CD8 relevant transcription factors including of IRF4, Myb and the Basic leucine zipper transcriptional factor ATF-like 3 (BatF3). Henceforth, our results suggest that small molecule inhibitors with dual specificity for PTP1B and TC-PTP are a powerful therapeutic tool for potentiating CTL cytotoxic responses and CTL based immunotherapies as CAR-T cells. Citation Format: Luis Alberto Perez-Quintero, Yevgen Zolotarov, Zuzet Martinez-Cardoba, Chu Han Feng, Alexandre Poirier, Kelly Anne Pike, Jean-Sebastien Delisle, Michel L. Tremblay. Concomitant reduction of PTPN1/PTPN2 activity synergistically enhanced antitumoral effector function of CD8 T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr NG16.