Differentiation fate of stem-like CD4 T cells control CD8 T cell immunity to cancer Restricted; Files Only
Cardenas Conti, Maria Andrea (Fall 2024)
Abstract
The T cell response to cancer controls disease progression and response to immunotherapy. Despite extensive knowledge regarding CD8 T cells, how CD4 T cells contribute to this process is less well understood. Here, we identified a population of PD1+TCF1+CD4 T cells with stem-like properties, capable of self-renewal and differentiation into canonical CD4 effector programs. Primarily residing within draining lymph nodes (TDLNs), these tumor-specific CD4 T cells are restricted by Tregs to a stem-like fate that predominantly generated iTregs, limiting effector CD8 T cell responses to the tumor. By contrast, upon Treg depletion, stem-like CD4 T cells differentiated into Th1 cells, and via IFNg production induced robust effector differentiation from TCF1+ CD8 T cells in TDLNs, a state we defined as “active”. Notably, enforcing Tbet expression in transferred stem-like CD4 T cells was sufficient to overcome the established restricted T cell state. Despite the presence of Tregs, endogenous stem-like CD4 T cells actively generated Th1 cells, which was required to restore TDLN effector CD8 T cell differentiation, enhance tumor control, and rescue response to immunotherapy. In agreement, kidney cancer patients with Th1 differentiation predicted successful immunotherapy responses and improved progression free survival. Together, these findings identify a stem-like CD4 T cell population that through alternative differentiation fates controls the switch between restricted and active T cell states with implications for cancer immunotherapies.
Table of Contents
TABLE OF CONTENTS
Abstract……………………………………………………………………………………………ii
Acknowledgements……………………………………………………………………………….iv
Table of Contents…………………………………………………………………………………vi
List of Figures…………………………………………………………………………………...viii
Chapter 1: Introduction………………………...……………………………………………….1
1.1 Introduction ………………………………………………….…………………..……………1
1.2 The plasticity of CD4 T cell responses ………..………………………………………………2
1.3 CD4 T cell differentiation in response to chronic antigen exposure……………………..……4
1.4 CD4 T cell differentiation in cancer – what we know and unanswered questions…………….8
Chapter 2: Differentiation fate of a stem-like CD4 T cell controls immunity to cancer……...9
2.1 Author’s Contribution and Acknowledgement of Reproduction……………………………….9
2.2 Abstract………………………………………………………………………………………..9
2.3 Introduction…………………………………………………………………………………..10
2.4 Results………………………………………………………………………………………..11
2.5 Discussion……………………………………………………………………………………64
2.6 Materials & Methods…………………………………………………………………………70
2.7 Acknowledgements…………………………………………………………………………..81
Chapter 3: Overcoming Stem-like CD4 T cell Tolerance Rescues Response to Cancer Vaccines………………………………………………………………………...………………..82
3.1 Author’s Contribution and Acknowledgement of Reproduction……………………………..82
3.2 Abstract………………………………………………………………………………………82
3.3 Introduction…………………………………………………………………………………..83
3.4 Results………………………………………………………………………………………..84
3.5 Discussion…………………………………………………………………………………..100
3.6 Materials & Methods………………………………………………………………………..102
CONCLUSIONS………………………………………………………………………………106
Chapter 4: References..………………………………………………………………………..108
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File download under embargo until 09 January 2027 | 2024-12-05 09:11:43 -0500 | File download under embargo until 09 January 2027 |
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