Understanding suppression of T effector memory cells by mediators of the ovarian carcinoma microenvironment

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Although CD8+ T cells have a beneficial impact on ovarian carcinoma survival, the tumor microenvironment, including the malignancy-associated peritoneal effusion (ascites), suppresses their function by largely unknown mechanisms. We recently identified a specific accumulation of CD8+ T effector memory (TEM) in ascites associated with a prolonged relapse-free survival (RFS) of patients. However, intracellular signaling molecules that are functionally crucial for T cell activation were suppressed by the ovarian carcinoma microenvironment in TEM cells, thereby leading to their dysfunction. The present cooperation project is based on this work and aims to elucidate the mediators, mechanisms and molecular markers of TEM suppression by ovarian carcinoma ascites. Toward this goal we have designed a systematic approach based on a combination of flow cytometric, biochemical, genetic, omics-based and bioinformatic tools. Our work program encompasses three specific objectives. (i) We aim to identify the specific soluble mediators in ascites that impinge on TEM signaling and function, using normal peripheral TEM cells as the experimental system. We will focus on mediators in ascites that are associated with poor RFS and have receptors on TATs. We will seek to identify further candidates by correlating ascites levels of specific mediators with the inhibition of TEM signaling, which already led to the identification of PD-L2 as a candidate. (ii) We plan to delineate the signaling molecules and pathways in primary TEM cells that transduce the inhibitory effect of PD-L2 and other specific mediators in ascites on TEM signaling by transcriptomic and proteomic approaches. We will compare the obtained data with the RNA and protein profiles of TEM cells from ascites with the goal to define clinically relevant diagnostic markers indicative of T cell “fitness” in patients. (iii) Based on this work, we will aim at rescuing TEM function and thus the delineation of novel therapeutically relevant targets, including the knock-down or pharmacological inhibition of negative signal transducers upregulated in response to mediators in ascites.We anticipate that this study will lead to an improved assessment of the functionality of CD8+ T cell in ovarian cancer patients, thereby providing a basis for novel diagnostic and individualized therapeutic approaches.