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 Gai-coupled chemokine
receptors will counter stimulatory G protein (Gas) 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.
