CD8 T cells with an exhaustion-like phenotype remain highly functional in hematologic tumors

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Presentation Time: 02:00 PM - 02:15 PM
Abstract ID: 5980 - B

Presenting Author:
Simone A Minnie , Postdoctoral Research Fellow at Fred Hutchinson Cancer Res. Ctr.

Abstract:

Loss of immunosurveillance in solid tumors is associated with CD8 T cell dysfunction/exhaustion (T_EX). Immunotherapies target T_EX differentiation, which may be modified by differences in microenvironments across cancer types and tissue sites. We characterized T_EX differentiation in bone marrow (BM), where liquid tumors reside, using mouse models of myeloma and B cell leukemia progressing after autologous stem cell transplantation and CD19-directed CAR T cells respectively. We used flow cytometry and concurrent analysis of RNA expression and DNA accessibility in single cells. We identified a novel CD8 T cell subset with a terminally exhausted phenotype that retained functional capacity, including secretion of cytotoxic molecules and IFNγ. These cells are referred to as interferon-Gamma-secreting, Phenotypically Exhausted (T_G-PhEX). Expression of functional genes in T_G-PhEX correlated with Batf expression and accessibility within the BATF motif. Chromatin remodeling in stemness associated genes indicated a loss of self-renewal capacity. Indeed, disease progression was associated with a lack of T_G-PhEX expansion and not dysfunction as T_G-PhEX effectively killed myeloma with comparable activity to CX3CR1⁺ T_EX. Importantly, we observed analogous cells in myeloma and lymphoma patients. T_G-PhEX are a clinically relevant target for immunotherapy of hematologic cancers and demonstrate differences in T_EX differentiation across tumor sites and cancer subtypes.