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Co-stimulation of T cell responses to nascent, emerging tumors

Award Number: R21CA286410
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/18/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Co-stimulation of T cell responses to nascent, emerging tumors - Abstract Immunosurveillance mechanisms in tissues eliminates pre-cancerous cells prior to formation of malignancies. This is supported by evidence from immunodeficient individuals where a much higher incidence of a variety of cancers have been reported compared with their immunocompetent counterparts. Empirical evidence from mice shows that effector mechanisms responsible for eliminating these emerging, nascent tumors primarily involve T cells and NK cells. In humans and mice, deficiencies in T cells numbers and/or molecules associated with T cell function such as STAT1, IFNγR1 or perforin, render hosts much more susceptible to developing cancers than immunocompetent individuals. How emerging, nascent tumors prime T cell responses has until recently remained an enigma and a major gap in knowledge. The Binder lab recently uncovered a pathway involving tumor-derived HSPs and the receptor CD91 expressed on APCs, that leads to priming of T cell responses to emerging, nascent tumors. In mice or humans with deficiencies of CD91 function in DC, T cell responses to nascent tumors are poorer than in mice/humans without CD91 deficiencies, allowing for the emergence of tumors. Our prior work has shown mechanistically that engagement of CD91 on APCs by tumor-derived HSPs leads to cross-presentation of HSP-chaperoned peptides (signal 1), and activation of signaling networks that provides co-stimulation (signal 2) and cytokines (signal 3). These three signals are essential for priming T cell responses and HSPs prime robust T cell responses in mice and humans. Our hypothesis is that tumor-derived HSPs deliver a signal to CD91 on APCs allowing for provision of co-stimulation and cytokines for T cell-mediated cancer immunosurveillance. We have previously shown in macrophages and DCs that two Tyrosines in the cytoplasmic tail of CD91 are important in initiating signaling pathways for cytokine elaboration and co-stimulation. In this proposal we will develop a new mouse model that conditionally expresses a non-signaling CD91 construct, to test the importance of CD91-mediated signaling in response to tumor-derived HSPs in the context of cancer immunosurveillance. Importantly, we shall use this mouse model to distinguish the role of CD91 in provision of co-stimulation from its other functions related to cancer immunosurveillance.


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 = $211,671 )
2026	2026	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	2	3/9/2026	NON-COMPETING CONTINUATION	$211,671
														Subtotal = $211,671

Issue Date FY: 2025 ( Subtotal = $176,712 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Cancer Treatment Research	000	1	3/18/2025	NEW	$176,712
														Subtotal = $176,712

Grand Total All Awards = $388,383

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Co-stimulation of T cell responses to nascent, emerging tumors

Award Number: R21CA286410

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/18/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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