dianas 10(1) > Arranz-Nicolás etal

dianas | Vol 10 Num 1 | marzo 2021 | e202103a01

Diacylglycerol kinase zeta limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes.

Javier Arranz-Nicolás^a, Miguel Martin-Salgado, Cristina Rodríguez-Rodríguez, Rosa Liébana, María del Carmen Moreno-Ortíz, Judith Leitner, Peter Steinberger, Antonia Ávila-Flores, Isabel Merida

Centro Nacional de Biotecnología (CNB-CSIC).

a. jarranz@cnb.csic.es

VI Congreso de Señalización Celular, SECUAH 2021.
29 de marzo a 30 de abril, 2021. Universidad de Alcalá. Alcalá de Henares, Madrid. España.

Keywords: Immunotherapy; Programmed Cell Death 1 Receptor; CD8+ T lymphocytes; Drug evaluation; Preclinical; Immune evation

Abstract

Background: The inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize anti-tumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hypo-responsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase zeta (DGKzeta) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKzeta deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKzeta function in human T cells, and no known inhibitors target this isoform.

Methods: We used a human triple parameter reporter (TPR) cell line to examine the consequences of DGKzeta depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKzeta deficiency on PD-1 expression dynamics, as well as the impact of DGKzeta absence on the in vivo growth of MC38 adenocarcinoma cells.

Results: We demonstrate that DGKzeta depletion enhances DAG-regulated transcriptional programs, promoting IL-2 production and partially counteracting PD-1 inhibitory functions. DGKzeta loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKzeta-deficient mice.

Conclusions: Our results, which define a role for DGKzeta in the control of PD-1 expression, confirm DGKzeta potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.