Proteomic profiling of exhausted T cells identifies novel immunotherapeutic targets

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B724
Abstract ID: 5484

Presenting Author:
Mohamed S. Abdel-Hakeem , Assistant Professor at Emory Univ. Sch. of Med., Winship Cancer Inst., Emory Univ.

Abstract:

Exhausted T cells (T_EX) are a hallmark of cancer and chronic viral infection, reflecting failure to clear tumors and viruses. Checkpoint blockade revolutionized immunotherapy by reinvigorating T_EX, however, not all cancer patients benefit from immunotherapy and responses are not durable. Thus, deeper understanding of molecular programs underlying the T_EX program is needed to identify novel therapeutic targets. Despite profiling transcriptional and epigenetic landscapes of T_EX, proteomic profiling of T_EX directly ex-vivo is lacking. Here, we sort purified LCMV-specific P14 T_EX at early, intermediate, and late phases of chronic infection by lymphocytic choriomeningitis virus clone 13 (LCMV-Cl13), and performed proteomic profiling of these cells using mass spectrometry. This was compared to the proteomic profile of effector/memory P14 cells (T_EFF/T_MEM) at the same time-points in the context of acute infection by LCMV Armstrong strain (LCMV-Arm). Our preliminary analyses identified many proteins, including several kinases, that are differentially abundant in T_EX compared to T_EFF/T_MEM which were not identified as top differential genes in transcriptional analyses, and represent promising therapeutic targets. To validate the role of the top differential proteins identified on T_EX biology, we deleted genes encoding these proteins in P14 cells prior to LCMV-Cl13 infection, and we are currently examining the impact on modulating T_EX differentiation and function.