Harnessing Adoptive Th17 Cell Immunotherapy: B Cell Cooperation with Potential Contextual Control Restricted; Files Only

Abstract

CD4⁺ T cells have emerged as mediators of durable responses to cancer immunotherapy; however, the optimal T helper subset and their mechanisms of tumor clearance remain unclear. We demonstrate that TRP-1 antigen–specific Th17 cell adoptive cell therapy (ACT) can achieve long-term tumor eradication and protection against metastatic spread through cooperation with host immunity. Unexpectedly, Th17 ACT required host B cells–but not host T cells–for sustained tumor clearance. B cells enhanced Th17 polyfunctionality, while Th17 cells provided IL-21 and CD40L signals that promoted B cell proliferation, activation, differentiation, and germinal center formation. This interplay resulted in the generation of class-switched, tumor-reactive antibodies that alone conferred partial protection against metastatic challenge. Together, these findings reveal that effective Th17 ACT depends on host B cells and a humoral immune response to sustain anti-tumor immunity.

 

Although Th17 ACT proved superior in melanoma, its efficacy in prostate cancer remained uncertain. Prostate tumors are immunologically “cold” and harbor suppressive endogenous Th17 cells, raising questions about whether this environment would blunt Th17 ACT. Using SMARTA Th17 cells targeting LCMV gp in a murine prostate cancer model, we found that Th17 ACT failed to reduce tumor burden, whereas Th0 ACT unexpectedly mediated regression. In the prostate cancer setting, Th17 cells produced a distinct cytokine milieu, including IL-17, IL-6, G-CSF, and KC, and recruited inflammatory myeloid cells to tumors and secondary lymphoid organs. These responses contrasted with the durable B cell dependent immunity observed in melanoma. Whether this diminished efficacy reflects tumor-intrinsic features of prostate cancer or differences in TCR transgenic models remains to be investigated.

 

Altogether, our findings highlight the context-dependent activity of Th17 ACT: in melanoma, Th17–B cell cooperation generates durable anti-tumor immunity, whereas in prostate cancer, Th17 driven inflammation promotes myeloid recruitment and fails to control tumor growth. Defining the mechanisms that govern these divergent outcomes will be critical for tailoring Th17-based immunotherapies across malignancies.

Table of Contents

Chapter 1: Introduction ---------------------------------------------------------------------------------------------- 1

1.1 The burden of cancer and the discovery of tumor immune surveillance ------------------------ 1

1.2 How the immune system kills tumors -------------------------------------------------------------------- 2

Introduction ------------------------------------------------------------------------------------------------------- 2

T cell recognition of tumors ---------------------------------------------------------------------------------- 3

CD8+ T cell effector mechanisms --------------------------------------------------------------------------- 4

CD4+ T cell effector mechanisms --------------------------------------------------------------------------- 4

B cell recognition of tumors ---------------------------------------------------------------------------------- 7

B cell effector mechanisms ---------------------------------------------------------------------------------- 8

Harnessing the adaptive immune system -------------------------------------------------------------- 12

1.3 Cancer immunotherapy approaches ------------------------------------------------------------------- 12

Adoptive Cell Therapy --------------------------------------------------------------------------------------- 13

1.4 Adoptive Th17 cell therapy ------------------------------------------------------------------------------- 16

1.5 Goals for this dissertation --------------------------------------------------------------------------------- 19

Chapter 2: Adoptively transferred Th17 cells cooperate with host B cells to achieve durable

tumor immunity ------------------------------------------------------------------------------------------------------ 20

2.1 Abstract -------------------------------------------------------------------------------------------------------- 20

2.2 Introduction --------------------------------------------------------------------------------------------------- 21

2.3 Results --------------------------------------------------------------------------------------------------------- 23

2.4 Discussion ---------------------------------------------------------------------------------------------------- 68

2.5 Materials and Methods ------------------------------------------------------------------------------------ 71

Chapter 3: Adoptively transferred Th17 cell therapy in prostate cancer lacks efficacy seen in

other tumors ---------------------------------------------------------------------------------------------------------- 93

3.1 Abstract -------------------------------------------------------------------------------------------------------- 93

3.2 Introduction --------------------------------------------------------------------------------------------------- 94

3.3 Results --------------------------------------------------------------------------------------------------------- 96

3.4 Discussion --------------------------------------------------------------------------------------------------- 106

3.5 Materials and Methods ----------------------------------------------------------------------------------- 111

Chapter 4: Conclusion and Closing Remarks --------------------------------------------------------------- 118

4.1 Summary ----------------------------------------------------------------------------------------------------- 118

4.2 Limitations and Future Directions ---------------------------------------------------------------------- 122

4.3 Path Towards Clinical Application ---------------------------------------------------------------------- 127

Chapter 5: References -------------------------------------------------------------------------------------------- 130

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Cancer Biology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, General
Keyword	Immunotherapy Cancer Immunology
Committee Chair / Thesis Advisor	Chrystal M. Paulos, Emory University
Committee Members	Gregory B. Lesinski, Emory University Sarwish Rafiq, Emory University Haydn T. Kissick, Emory University Jeremy M. Boss, Emory University

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