Cellular and Molecular Mechanisms Underlying T Cell Differences 

in PD-1 Sensitivity

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B619
Abstract ID: 4925

Presenting Author:
Anchala A Rao , Student Researcher at Icahn Sch. of Med., Mount Sinai

Abstract:

Research into basic PD-1 biology, together with the clinical picture of cancer patients treated with PD-1 blocking antibodies, converge to emphasize that PD-1 engages complex signaling networks to support T cell homeostasis, differentiation, and immune responses. Despite its key role, there is a lack of understanding in: the molecular cascades that drive sensitivity and resistance to PD-1 in functionally distinct human T cells.

We use a combination of functional immuno-assays, transcriptional and proteomic profiling to identify differences in PD-1 signaling across the trajectory of naïve-to-memory T cell differentiation.

We show T cell subsets and ligand specific differences in PD-1 inhibition observed at a functional and transcriptional level. While PD-1 inhibited IL2 production from both CD4 and CD8 T cells, we observed a significant difference in the magnitude of IL-1 inhibition and T cell proliferation between PD-L1 and PD-L2 in CD4 but not in CD8 T cells. These differences were specific to naïve and central memory CD4 and driven by the suppression of NFAT and E2F target genes associated with cytokine production and cell cycle regulation. In contrast, in naïve CD8 T cells PD-1 targeted genes associated with cellular metabolism while effector subsets of CD4 and CD8 T cells were less sensitive to PD-1. 

Our findings help elucidate the cellular and molecular etiologies associated with PD-1 inhibition that will help us understand patient responses to PD-1 immunotherapies.