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Identifying mechanisms underlying biologic sex-based differences in tumor-associated CD4+ T cell help

Award Number: R37CA306974
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Identifying mechanisms underlying biologic sex-based differences in tumor-associated CD4+ T cell help - PROJECT SUMMARY While biologic sex is known to impact immune responses in the contexts of infectious disease and vaccination, little is understood regarding differences between the male and female immune response to cancer. Initial reports have shown for the first time that sex-based differences in the immune system contribute to greater cancer incidence in males, but these studies have focused almost entirely on CD8+ T cells. CD4+ T cells play vital roles in orchestrating immune responses that can either promote or inhibit tumor progression. Therefore, there is a critical need to understand how sex impacts CD4+ T cell function in cancer. Our long-term goal is to define how sex-based differences in antitumor immunity contribute to disparities in cancer incidence and disease outcomes. To achieve this, our overall objective is to elucidate mechanisms that drive disparate CD4+ T cell function between males and females. The rationale that underlies our proposed research is that uncovering the mechanisms regulating sex-based differences in the CD4+ T cell response against cancer may uncover therapeutic targets that can be manipulated to promote better immune-mediated tumor control in patients. Our central hypothesis is that reduced tumor-associated T cell help in males is the result of decreased CD40L-CD40 signaling driven by direct regulation of CD4+ T cells by the androgen receptor (AR). To achieve our objective, we will pursue the following specific aims: 1) Define the driver(s) of impaired CD40L-CD40 signaling in males; 2) Determine how sex differences in CD40L-CD40 signaling impact dendritic cell (DC)-mediated T cell priming and polarization; and 3) Determine how biologic sex drives differences in tumor-associated CD4+ T cell function. In Aim 1, we will identify the relative contributions of CD4+ T cells and DCs to reduced CD40L-CD40 signaling in males using in vivo monitoring of CD40L-CD40 interactions, and highly controlled in vitro modeling. In Aim 2, we will identify a mechanistic link between reduced CD40L expression in males and sex differences in intratumoral CD4+ T cell function by defining the impact on DC expression of Th-1 polarizing molecules. In Aim 3, we will define the role of AR in regulating CD4+ T cells using CD4+ T cell specific knockout of AR and chromatin immunoprecipitation (ChIP)-sequencing. This application is innovative because it approaches the question of sex-based differences in tumor immunity from the novel perspective of CD4+ T cells and evolves our understanding of how biologic sex impacts antitumor immunity beyond the current minimal understanding. The proposed research is significant because sex disparities in CD40L-CD40 signaling may represent an unappreciated central hub through which sex broadly impacts both CD4+ and CD8+ T cell responses against cancer. It will also provide justification for future clinical exploration of AR inhibition as a novel CD4+ T cell-targeting therapy. The complexity of the mammalian immune system, along with poorly understood effects of biologic sex on immune function, limits the ability to address our hypotheses in vitro, in simpler species, or using existing in silico models. Therefore, murine models were selected because they reflect sex-based disparities observed in comparable human cancers.


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 = $504,955 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Cancer Biology Research	000	1	6/19/2026	NEW	$504,955
														Subtotal = $504,955

Grand Total All Awards = $504,955

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Identifying mechanisms underlying biologic sex-based differences in tumor-associated CD4+ T cell help

Award Number: R37CA306974

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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