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The role of Galectin-1 in shaping the immune suppressive landscape in head and neck cancer

Award Number: R01DE029672
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract Head and neck squamous cell carcinoma (HNSCC) is the 9th most common cancer globally. Studies have shown that tumor-induced suppression of the host immune system is critical to HNSCC progression and metastasis. Tumor secreted factors directly influence the expansion of myeloid-derived suppressor cells (MDSC), which have emerged as forefront mediators of cancer immune suppression. MDSC not only promote tumor growth by suppressing T cells within the tumor, but also facilitate metastasis by enhancing angiogenesis and pre-metastatic niche formation. The presence of expanded MDSC peripherally and within the tumor microenvironment has been associated with worse prognosis with definitive treatment and less response to anti-PD1 immune checkpoint therapy in HNSCC. Moreover, RT itself has been shown to increase MDSC level systemically. Therefore, investigating factors that facilitate MDSC expansion, recruitment and function is integral to developing novel therapies. We have previously shown that Galectin-1 (Gal-1) is induced by hypoxia and/or RT in HNSCC and its elevated expression in the tumor stroma correlated with poor prognosis. We have data indicating that Gal-1 expressing tumors harbor high levels of local and systemic MDSC, and that Gal-1 blockade (genetically or with antibodies) substantially reduced the number of MDSC throughout, independent of its effect on T cells. Moreover, Gal-1 blockade led to fewer metastases and less MDSC recruitment to metastatic sites. Despite extensive literature supporting Gal-1’s effect on T cells, very few studies have evaluated its relationship with MDSC. Based on our preliminary data, we hypothesize that tumor secreted Gal-1 can directly affect MDSC recruitment to the primary tumor while simultaneously promote metastases through MDSC driven pre-metastatic niche formation. In addition, RT-induction of Gal-1 secretion may lead to higher systemic MDSC noted in patients receiving RT. Therefore, Gal-1 blockade can decrease both local and systemic MDSC burden and enhance tumor response to both RT and immune check point therapy. We will test this hypothesis with the following specific aims: (1) To determine whether Gal-1 mediates the effect of RT on increasing MDSC level in the tumor and systemwide in HNSCC; (2) To discern the host versus tumor cell dependent factors mediating Gal-1’s induction of MDSC expansion systemwide and recruitment to the tumor microenvironment; (3) To determine whether MDSC mediate Gal-1’s effect on metastases and whether CXCR2 blockade decrease distant metastasis in Gal-1+ HNSCC, and (4) To determine whether CXCR2 inhibition is as effective as Gal-1 blockade when combined with RT and PD1 antibody in HNSCC and to characterize the immune cells involved in these treatments. While optimal Gal-1 targeting is being developed, clinical grade CXCR2 inhibitors exist and are being tested in trials for both cancer and non-cancer conditions. Our studies, if successful, will provide rationales for integrating CXCR2 inhibitor with RT and anti-PD1 therapy in Gal-1 overexpressing HNSCC.


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: 2024 ( Subtotal = $518,764 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	4	2/6/2024	NON-COMPETING CONTINUATION	$518,764
														Subtotal = $518,764

Issue Date FY: 2023 ( Subtotal = $576,376 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	3	2/14/2023	NON-COMPETING CONTINUATION	$576,376
														Subtotal = $576,376

Issue Date FY: 2022 ( Subtotal = $570,587 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	001	2	4/21/2022	NON-COMPETING CONTINUATION	$51,875
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	2	2/9/2022	NON-COMPETING CONTINUATION	$518,712
														Subtotal = $570,587

Issue Date FY: 2021 ( Subtotal = $574,961 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	001	1	4/15/2021	NEW	-$1,204
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Oral Diseases and Disorders Research	000	1	4/14/2021	NEW	$576,165
														Subtotal = $574,961

Grand Total All Awards = $2,240,688

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The role of Galectin-1 in shaping the immune suppressive landscape in head and neck cancer

Award Number: R01DE029672

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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