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Targeting Tr1 to enhance the efficacy of cancer vaccines

Award Number: R21CA313364
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/14/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Targeting Tr1 to enhance the efficacy of cancer vaccines - PROJECT SUMMARY Background: Neoantigen cancer vaccines have shown promising clinical potential in preventing or delaying tumor recurrence in a fraction of people. The low efficacy of neoantigen cancer vaccines can be attributed to several reasons, including the low abundance of antigen-specific CD8 T cell responses induced by these therapies. Additionally, accumulating evidence suggests that suppressive cells such as Foxp3+ Tregs or Foxp3-negative type 1 regulatory CD4 T cells (Tr1) are profoundly immunosuppressive and function as a major obstacle to cancer vaccine-induced antitumor responses. Our recent publication in Nature demonstrated that the antitumor efficacy of neoantigen cancer vaccines depends on the peptide dose of MHC-II–restricted neoantigens included in the vaccine formulation. Whereas vaccines comprised of MHC-I restricted neoantigens plus low doses of MHC-II-restricted neoantigens (LDVax) promote tumor rejection, similar vaccines containing high doses of the same MHC-II neoantigen (HDVax) induce Tr1 cells and inhibit rejection. Notably, CD4 T cells with a Tr1-like signature have been detected in cancer patients and correlate with poor patients’ outcome. Objective/Hypothesis: Our preliminary studies indicate that neoantigen cancer vaccines containing high doses of altered peptide ligands (APLs) with low MHC-II binding affinity do not induce Tr1 cells and instead promote tumor rejection. Additionally, Tr1 induction also required antigen presentation by type 2 dendritic cells (cDC2) and the participation of signaling by EBI3 subunit of the inhibitory cytokine IL-35. Based on these findings, we hypothesize that DC2/monocyte-derived IL-35 synergize with strong interactions between peptide and MHC-II molecules and T cell receptors (pMHC: TCR) to drive Tr1 cell induction and thereby inhibit the antitumor efficacy of neoantigen cancer vaccines. Specific Aims: (1) Elucidate the role of the EBI3 cytokine subunit chain of IL-35 in the induction of Tr1 cells; and (2) Define the factors that regulate expression of IL-35 signaling receptors (IL-12Rβ2 and IL-27Rα) required for Tr1 cell induction. Study design: Using our well characterized tumor models, we will identify the cellular sources of IL-35 using IL-35 reporter mice and assess how IL-35 blockade alters the phenotype and effector function of Tr1 and CD8 T cells. We will test whether IL-35 neutralization enhances vaccine-driven tumor rejection by diminishing Tr1-mediated suppression and boosting CD8 T cell cytotoxicity. We anticipate that IL-35 blockade will reduce Tr1 differentiation, reprogram CD4 T cells toward a Th1 phenotype, and enhance CD8 T cell effector responses. In Aim 2, we will determine whether strong pMHC: TCR interaction favors the differentiation of tumor-specific CD4 T cells into Tr1 cells by upregulating IL-12Rβ2 and IL-27Rα receptors involved in the signaling of IL-35. We expect that stronger interaction in CD4 T cells correlates with Tr1 differentiation and suppression of antitumor immunity.


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 = $399,829 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	5/14/2026	NEW	$399,829
														Subtotal = $399,829

Grand Total All Awards = $399,829

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Targeting Tr1 to enhance the efficacy of cancer vaccines

Award Number: R21CA313364

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/14/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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