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Dissecting CCL5 contribution to antigen specific T cell responses in head and neck cancers

Award Number: R01DE034386
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/21/2025
PERIOD OF PERFORMANCE END DATE: 08/20/2029

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Dissecting CCL5 contribution to antigen specific T cell responses in head and neck cancers - PROJECT SUMMARY Correlative studies of immune checkpoint blockade (ICB) show that response is highly dependent on the quantitative and qualitative status of pre-existing antitumor T cell clones. Of particular importance is the reservoir of tissue resident memory (TRM) T cells that positively correlate with response to ICB therapies. Our work in head and neck squamous cell carcinomas (HNSCCs) leads us to hypothesize that TRM T cells are major players in the early anti-tumor immune response to immunotherapy and that identifying specific chemokine and cytokine networks shaping the development and functionality of antitumor TRM cells will lead to improved therapeutic strategies. Using scRNASeq and scTCRseq of baseline and on treatment tumor samples from a novel neoadjuvant anti-PD1 HNSCC clinical trial (NCT02296684), we demonstrated that responding tumors had clonally expanded putative tumor specific exhausted CD8+ TILs with a TRM program, characterized by high cytotoxic potential and ZNF683 expression. By contrast, the non-responder baseline tumor microenvironment (TME) exhibited relative absence of cytotoxic ZNF683+ TILs and accumulation of highly exhausted clones. To define the determinants of TRM-development, we pursued mechanistic studies using anti-PD1 responsive or resistant HNSCC cell line syngeneic mouse models. This work confirmed that antitumor TRM-cell activity was positively correlated with increased frequency and functionality of type 1 conventional dendritic cells (cDC1) and with enhanced CCL5 chemokine expression in both human HNSCCs and mouse models. To expand our understanding of TME and tumor draining lymph node specific CCL5 dependent mechanisms underlying productive or ineffective T cell responses against HNSCC, we will dissect CCL5 driven remodeling of the TME including defining cellular sources and its target(s). We will extend these studies to human HNSCCs to dissect CCL5 and CCR5 contributions to DC:T cell interactions in fresh tumor explants. Finally, we will use a therapeutic approach with a novel oncolytic virus targeted to epidermal growth factor expressing tumor cells that anchors CCL5 in the TME. Together, this work will address the knowledge gap regarding the factors underlying cytotoxic versus dysfunctional antitumor tumor infiltrating lymphocytes in the HNSCC TME.


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: 2025 ( Subtotal = $3,742,682 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Oral Diseases and Disorders Research	000	1	8/21/2025	NEW	$3,742,682
														Subtotal = $3,742,682

Grand Total All Awards = $3,742,682

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Dissecting CCL5 contribution to antigen specific T cell responses in head and neck cancers

Award Number: R01DE034386

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/21/2025

PERIOD OF PERFORMANCE END DATE: 08/20/2029

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