Abstract A207: PD-1-functionality and CD28 molecule expression in CD8+ T-cells of cancer patients

The main objective of cancer immunotherapy is an efficacious control over tumor progression through the generation of a strong and persistent T-cell mediated immune response. T-cells constantly exposed to tumor-associated antigens experience phenotypic and functional changes, acquiring a dysfunctional state due, at least in part, to the expression of co-inhibitory receptors including Programmed Death 1 (PD-1). Nevertheless, recently it has been demonstrated that the main downstream target of PD-1-mediated signaling is CD28, opening an important implication for the immune checkpoint blockade in cancer immunotherapy. Recently we have demonstrated that CD8+ T-cell anti-tumor functional advantage induced by combined chemotherapy before peptide-vaccination is determined by tumor antigen nature, immune-checkpoint phenotype, TCR repertoire diversity and antitumor lytic capability. In particular, in accordance with several recent studies, we have observed that in Ag-specific CD8+ T-cells the co-expression of PD-1 with CD28 confers an exhausted phenotype and a defective antitumor functionality, that may be reverted by the blockade of PD-1, while a subset of Ag-specific CD8+ T-cell clones characterized by high levels of PD-1 in the absence of CD28, and the presence of ICOS, showed high proliferative capability and an AKT-dependent antitumor functionality sustained by ICOS (1-3). Herein, to better elucidate the role of PD-1 in CD8 T-cell differentiation and function, we show that, differently from functional PD1-positive/CD28-negative T-cells, Ag- specific CD8+ T-cell clones are not polyfunctional, not able to lyse tumor cells and did not possess an active AKT pathway when PD-1 and CD28 were co-expressed. This suggests that the AKT kinase was activated in these T-cells expressing PD-1 but not CD28. To clarify the complex role of PD-1 in regulating T-cell functionality on the basis of our observations obtained in tumor Ag-specific CD8+ T-cell clones, we have analyzed the phenotypic and functional distribution of CD8+ T-cells, with respect to PD-1 and CD28 expression, in patients with different types of cancer. Preliminary results indicate that functional distinct PD-1/CD28 CD8+ T-cell subsets can be found in peripheral blood of cancer patients with a pattern of functionality similar to that identified in CD8 T-cell clones. Furthermore, to identity whether the lung tumor microenvironment may influence the frequency and functionality of these T-cell populations, we have compared these subsets in the periphery and tumor site in lung cancer. These results may clarify the complex role of PD-1 in regulating T-cell functionality and may provide a significant perspective for exploiting the functional significance of T-cell subsets defined by PD-1/CD28 expression, to predict and monitor tumor responsive T-cells during immunotherapy treatments based on PD-1 blockade.§ B.P. and O.F. contributed equally to this work. References: 1. Palermo B, Franzese O, et al. OncoImmunology. In press. https://doi.org/10.1080/2162402X.2018.1465163. 2. Franzese O, Palermo B, et al. OncoImmunology 2016. Feb 1;5(5):e1114203. 3. Palermo B, et al. Cancer Res 2010 Sep 15;70(18):7084-92. Citation Format: Belinda Palermo, Ornella Franzese, Mariangela Panetta, Virginia Ferraresi, Gabriele Alessandrini, Franco Facciolo, Gennaro Ciliberto, Paola Nistico. PD-1-functionality and CD28 molecule expression in CD8+ T-cells of cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A207.