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Unraveling the immunobiology of tumor-specific T follicular helper CD4 T cells

Award Number: F30CA310070
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/30/2026
PERIOD OF PERFORMANCE END DATE: 09/29/2027

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Unraveling the immunobiology of tumor-specific T follicular helper CD4 T cells - PROJECT SUMMARY While immune checkpoint blockade therapies have revolutionized the treatment of cancer for patients, many remain unresponsive. There has been increased focus on factors outside of tumor-infiltrating CD8 T cells that contribute to treatment efficacy, particularly the role of helper CD4 T cells. In investigating this question, current studies have identified the CD4 subset, T follicular helper cells and their canonical cytokine Interleukin (IL)-21, to be an important driver of response, particularly to the CTLA-4 axis of immunotherapy. These studies, however, fail to define the precise location of IL-21 delivery for optimal CD8 T cell help or additional required factors, including the generation tumor-specific B cells. Based on preliminary data that tumor draining lymph nodes (tdLNs) contain a reservoir of IL-21 producing CD4 T cells outside of B cell follicles and that CTLA-4-mediated IL-21 production depends on a B cell antigen, I hypothesize that in order to optimally prime CD8 T cells to generate antitumor effectors and respond to CTLA-4, IL-21 production must occur outside of the B cell follicle in tdLNs and that this depends on the presence of tumor-specific B cells. To directly test this, I will pursue the following aims. For my first aim, I will define the factors that give rise to the subset of IL-21+ CD4 T cells in the extrafollicular zone of tdLNs. To accomplish this, I will spatiotemporally track the location, phenotype, and path of differentiation of IL-21-producing cells in tdLNs by cyclic immunofluorescence, flow cytometry, and single cell RNA sequencing. I will target genes predicted to be involved in this differentiation path using Cas9 ribonucleoprotein editing of tumor-specific CD4 T cells to modify their development and function. For my second aim, I will determine the role of IL-21 production on CD8 T cell effector function and anti-CTLA-4 therapeutic efficacy. To do this, I will eliminate the ability to produce IL-21 in tumor-specific CD4 T cells or remove B cells and determine the effects on CD8 T cell effector function and CTLA-4 blockade efficacy. I will then use adoptive transfer studies with a model of lung adenocarcinoma that is capable of generating IL-21+ TFH, HELLO, and one that is not, NINJA, to assess the requirement of CD4 interactions with tumor-specific B cells for CTLA-4 immunotherapy responses. Lastly, I will directly deliver tumor-specific CD4 T cells with ectopic IL-21 expression to NINJA tumor-bearing mice to overcome the requirement of B cells. I expect that my findings will uncover the necessary factors for productive IL-21 delivery within tdLNs and identify new strategies to generate IL-21 producing cells and reinvigorate CD8 T cells in ICB unresponsive tumors.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $33,384 )
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	001	1	4/16/2026	NEW	$576
2026	2026	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cancer Research Manpower	000	1	3/30/2026	NEW	$32,808
														Subtotal = $33,384

Grand Total All Awards = $33,384

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Unraveling the immunobiology of tumor-specific T follicular helper CD4 T cells

Award Number: F30CA310070

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/30/2026

PERIOD OF PERFORMANCE END DATE: 09/29/2027

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