Synergistic Paradigm of Radiotherapy and PD-L1 Blockade Orchestrates the Induction of Stem-Like T Cell Populations within the Tumor-Draining Lymph Node Open Access

Abstract

Combined Radiotherapy (RT) and anti-PD-L1 therapies are known to augment control of both local and distant (abscopal) tumors. Variability exists in human clinical responses, however, which necessitates a deeper exploration of the cooperative mechanisms involved. This investigation targets the synergistic interactions between RT and anti-PD-L1 at the cellular level, specifically focusing on the role of a CD8+ PD-1+ Tcf-1+ stem-like T cell population within the tumor-draining lymph node (TdLN). Experimental designs employing melanoma murine models have revealed that simultaneous administration of RT and anti-PD-L1 orchestrates a unique program of differentiation within TdLN stem-like T cells. This program catalyzes their expansion and differentiation into intratumoral effector cells within the tumor microenvironment. Our data also suggest that the enhanced antitumor efficacy arising from the combination of RT and anti-PD-L1 critically hinges on the integrity and functionality of the stem-like T cell population in the TdLN. Impediments to the migratory egress of these cells from the TdLN or the targeted depletion of this specific subset attenuate the therapeutic efficacy. This study elucidates a complex, phased induction process of stem-like T cells beginning within the TdLN and reaching completion within the tumor microenvironment, fundamental to the combined treatment's effectiveness.

Table of Contents

Background Information 1         

Results and Figures 4

Figure 1. Combining RT and anti-PD-L1 Therapy Elevates Intratumoral Stem-Like and Terminal Effector CD8+ T Cell Populations 5                      

Figure 2. TdLN Serves as a Reservoir of Stem-Like CD8+ T Cells and Supplies the Tumor After RT + Anti-PD-L1 Therapy 7               

Figure 3. RT and Anti-PD-L1 Therapy Reprogram CD8+ T-cell Gene Expression Profiles in the TdLN 9                                                                               

Figure 4. RT Enhances the Expansion and Differentiation of TdLN Stem-Like T Cells, Further Augmented by Anti-PD-L1 10

Discussion 12

Methods 14

References 17

Supporting Figures 20

Figure S1. RT combined with anti-PD-L1 enhances tumor suppression and boosts the presence of IFNγ+ CD8+ T cells within the tumor 21                                                                                 

Figure S2. FTY720 treatment negated the increase in Gp33+ T cells and weakened the tumor growth control achieved by RT or anti-PD-L1 22                       

Figure S3. FTY720 administration elevated the presence of Gp33+ T cells and the quantity of stem-like T cells in the TdLN 23                                                     

Figure S4. RT and anti-PD-L1 therapy together enhance the proliferation and differentiation of stem-like T cells 24

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Health Sciences, Oncology Health Sciences, Immunology Biology, General
Keyword	Tumor-draining lymph node Checkpoint blockade Tcf-1 PD-1 Stem-like T cells Immunotherapy Abscopal effect PD-L1
Committee Chair / Thesis Advisor	Zachary S. Buchwald, Emory University
Committee Members	Cora E. MacBeth, Emory University Richard A. Himes, Emory University

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