Participating Experts: Andrea Schietinger, PhD (MSKCC), Benjamin A. Youngblood, PhD (St. Jude Children’s Research Hospital)
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Download the T Cell Exhaustion Multiplex IHC Application Note: https://cst-science.com/92ekl6
Cancers escape normal immune surveillance through several pathways. For example, T cells isolated from tumors have been found to be dysfunctional, opening the door to possible immunotherapy interventions, such as immune-checkpoint inhibitors. However, significant clinical responses to immunotherapy have been observed in only a subset of patients and cancer types. T-cell exhaustion is another variable at play, resulting in reduced efficacy of the immune system in removing cancerous cells. To address these clinical challenges and design predictably effective cancer treatments, we must elucidate the precise underlying regulatory mechanisms that determine tumor-specific T-cell functional states and their potential for therapeutic reprogramming. In this webinar, we review the underlying mechanisms and epigenetic programs determining tumor-specific T-cell dysfunction and reprogrammability and discuss current challenges and outstanding research questions in cancer immunotherapy.
Table of Contents
0:39 Welcome and overview
2:42 Benjamin Youngblood speaker profile
3:17 T cell intrinsic and extrinsic mechanisms limiting tumor immunotherapy
4:25 Global reprogramming of gene expression during effector and memory CD8 T cell differentiation
7:39 What limits the efficacy of T cell based immunotherapies?
9:28 Maintenance of T cell exhaustion after prolonged exposure to antigen
11:29 How are long-lived gene expression programs maintained in exhausted CD8 T cells?
12:50 Epigenetic barriers of T cell-based immunotherapies
13:51 Does de novo epigenetic programming regulate T cell exhaustion?
15:23 T cell exhaustion is limited in Dnmt3a deficient CD8 T cells
17:24 De novo epigenetic programs restrict T cell expansion during PD-1 blockade therapy
18:47 ICB therapy in combination of Dnmt3a deletion results in heightened viral control
19:39 Decitabine treatment enhances expansion of exhausted CD8 T cells after PD1 blockade
20:54 Long-lived human memory CD8 T cells maintain a posed effector response during homeostatic proliferation
25:03 Defining the human T cell differentiation epigenetic landscape
29:13 Overcoming mechanisms that limit T cell responses during immunotherapy
29:40 Summary, implications, and future directions
31:15 Andrea Schietinger speaker profile
31:47 CD8 T cell differentiation
32:33 CD8 T cell dysfunction in tumors
34:55 Tumor-specific T cells become dysfunctional early during tumorigenesis
37:28 Chromatin state dynamics of tumor-specific CD8 T cells during tumorigenesis
39:50 Plastic and fixed chromatin states can be identified by unique surface membranes/biomarkers
42:18 Thymocyte selection-associated HMG box protein Tox is uniquely expressed in dysfunctional tumor-specific cells
44:24 Chromatin accessibility of Tox locus
45:35 What is the role of TOX during tumor-specific T cell differentiation?
47:16 TOX-induced exhaustion phenotype is required for T cell survival in tumors
49:25 Questions and answers
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