Stem-like Tcf1+PD-1+CD8+ T cells are required for an optimal abscopal effect stimulated by combined radiation and anti-PD-L1 therapy Pubblico

Abstract

Not only a local cancer treatment, radiotherapy (RT) also induces global antitumor immunity and occasionally, the abscopal effect, an immune-mediated occurrence in which non-irradiated metastases shrink together with the irradiated tumor. Despite that the RT-induced abscopal effect could be enhanced by PD-1/PD-L1 checkpoint inhibitors, which evade T cell exhaustion by acting on tumor-infiltrating, stem-like Tcf1+PD-1+CD8+ T cells, the immune landscape behind this combined treatment remains poorly understood. Here we show that these intratumoral Tcf1+PD-1+CD8+ progenitor exhausted T cells are required for the optimal abscopal effect stimulated by combined RT and PD-L1 blockade. Depletion of this stem-like subset curtailed the previously enhanced abscopal effect and reversed the tumor control in both irradiated and unirradiated sites. In addition, we find that combined RT and PD-L1 inhibitors curbed tumor growth more effectively than monotherapy, and that this combined regimen expanded intratumoral Tcf1+PD-1+CD8+ T cells, which exhibited the proliferation capacity to differentiate into more cytotoxic and terminally exhausted effector T cells. Thus, our findings reveal that the stem-like Tcf1+ progenitor exhausted population may serve as a critical target for improving the clinical response to radiation and immune checkpoint blockade. 

Table of Contents

INTRODUCTION .......................................................................................................................... 1

Radiotherapy (RT) and the abscopal effect ...................................................................................... 1

Radiotherapy-induced immune responses and the immune-mediated abscopal effect ........................1

T cell exhaustion and PD-1/PD-L1 checkpoint inhibitors ................................................................. 4

Enhancement of the abscopal effect by PD-1/PD-L1 checkpoint inhibitors ........................................ 7

Stem-like Tcf1+PD-1+CD8+ TPEX cells and terminally differentiated Tim-3+PD-1+CD8+ TEX cells .....8

Key question ............................................................................................................................... 11

METHODS .................................................................................................................................. 12

Mice ........................................................................................................................................... 12

Tumor cell lines ........................................................................................................................... 13

Tumor implantation and tumor volume and weight measurements.................................................. 13

Adoptive T cell transfer ................................................................................................................ 14

Radiation .................................................................................................................................... 14

PD-L1 blockade and diphtheria toxin (DT) treatment ..................................................................... 14

Tumor digestion and preparation of single-cell suspensions......................................................... .. 15

Surface and intracellular staining and flow cytometry .................................................................... 16

Statistical analysis....................................................................................................................... 17

RESULTS ...................................................................................................................................................................................................................................................... 18

DT treatment post DTR gene knock-in at Tcf7 locus depleted intratumoral and TDLN-resident Tcf1+PD-1+CD8+ TPEX cells ................................................................................ 18

The stronger tumor control and abscopal effect stimulated by combined RT and anti-PD-L1 therapy were curtailed after depletion of Tcf1+PD-1+CD8+ TPEX cells ........................ 25

RT in combination with PD-L1 blockade augmented intratumoral GzmB(lo)Tcf1+ TPEX cells in both primary and abscopal tumors ....................................................................... 31

DISCUSSIONS............................................................................................................................. 36

AUTHOR CONTRIBUTION........................................................................................................... 38

REFERENCES ............................................................................................................................. 39 

About this Honors Thesis

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School	Emory College
Department	Biology
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Biology, General Health Sciences, Immunology Health Sciences, Oncology
Parola chiave	CD8+ T cells Tcf1 checkpoint blockade progenitor exhausted T cells abscopal effect immune checkpoint inhibitors radiation immunotherapy radiotherapy PD-1/PD-L1 T cell exhaustion
Committee Chair / Thesis Advisor	Buchwald, Zachary S. , Emory University
Committee Members	Kissick, Haydn T. , Emory University Rieder, Leila, Emory University

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