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.