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Reprogramming the Tumor Immune Microenvironment with Chemokines to Potentiate Immune Oncology Treatments in Oral Cancer

Award Number: R01DE033909
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: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Reprogramming the Tumor Immune Microenvironment with Chemokines to Potentiate Immune Oncology Treatments in Oral Cancer - Head and neck squamous cell carcinoma (HNSCC) is a significant global health problem with high mortality rates. HPV-negative HNSCC patients undergo morbid treatments combining surgery, radiation, chemotherapy and molecularly targeted therapy, but the 5-year survival rate is low (63-68%) and even lower (<50%) for locally advanced disease, and has remained unchanged during the last four decades. Indeed, although immunotherapies have revolutionized the landscape of treatment options, <20% of HNSCC patients respond to immune check point blockade (ICB); thus new therapeutic options to prevent and treat HNSCC are urgently needed. A major reason for the poor response rate to ICB therapy is that HNSCC tumors deploy multiple mechanisms that culminate in a highly immune suppressive tumor microenvironment (TME) deficient in cytotoxic and antigen presenting immune cells that are required for tumor elimination and ICB treatment efficacy. Accordingly, we hypothesize that intratumoral priming with chemokines that recruit and activate cytotoxic CD8 T and NK cells, and antigen presenting conventional dendritic cells (cDCs), will dramatically improve ICB treatment responses and patient outcomes. We also hypothesize that activation of their inhibitory Gαi-coupled chemokine receptors will counter stimulatory G protein (Gαs) signaling mechanisms that lead to T cell exhaustion and cDC dysfunction. In this proposal we will employ novel syngeneic mouse models of HNSCC that closely mimic the human tobacco-associated disease to investigate the anti-tumoral efficacy of two chemokines: (i) CXCL10, a chemokine that recruits and activates cytotoxic CD8 T and NK cells through the chemokine receptor CXCR3 and (ii) XCL1 which recruits and activates conventional dendritic cells (cDCs) through the receptor XCR1. These chemokines will be investigated as single agent treatments (Aim 1 and 2) and as priming agents, individually and combined with anti-PD-1. In addition to the effect of these treatments on tumor growth, the abundance and phenotype (e.g. pro- or anti-tumoral properties, activation or dysfunction) of the TME immune infiltrate will be determined using state-of-the-art quantitative profiling methods and functional assays. Intratumoral location, spatial distribution, clustering and trafficking of cells between tumors and tumor draining lymph nodes will also be determined. Although a major focus will be on cells directly affected by CXCL10 and XCL1, the extent to which these chemokines broadly reprogram the TME as a consequence of interconnected signaling networks and cell-cell communication will also be explored. Our overall premise is that the chemokine system can be harnessed to override immune suppressive mechanisms deployed by cancer cells, thereby potentiating ICB responses. This premise is supported by strong preliminary data in all three Aims. Our ultimate goal is to provide viable treatment options for HNSCC patients by exploiting chemokine priming to dramatically enhance the efficacy of existing ICB treatments, and to understand the underlying mechanisms for their success.


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 = $574,900 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	3	1/29/2026	NON-COMPETING CONTINUATION	$517,411
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Oral Diseases and Disorders Research	001	3	4/16/2026	NON-COMPETING CONTINUATION	$57,489
														Subtotal = $574,900

Issue Date FY: 2025 ( Subtotal = $585,606 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Oral Diseases and Disorders Research	001	2	5/7/2025	NON-COMPETING CONTINUATION	$58,561
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	2	2/13/2025	NON-COMPETING CONTINUATION	$527,045
														Subtotal = $585,606

Issue Date FY: 2024 ( Subtotal = $595,600 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Oral Diseases and Disorders Research	000	1	2/22/2024	NEW	$595,600
														Subtotal = $595,600

Grand Total All Awards = $1,756,106

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Reprogramming the Tumor Immune Microenvironment with Chemokines to Potentiate Immune Oncology Treatments in Oral Cancer

Award Number: R01DE033909

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: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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