Novel Targets for Immunotherapy

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Head and neck squamous cell carcinomas (HNSCC) are tumors that originate in the epithelial cells of the mucosa of the oral cavity, pharynx, and larynx. While most cases of HNSCC are associated with exposure to tobacco-derived carcinogens and alcohol consumption (HPV-negative HNSCC), a subset of these tumors are associated with high-risk human papillomavirus (HPV) infection (HPV-positive HNSCC). At diagnosis, a large fraction of patients with HPV-negative and HPV-positive HNSCC present with locally advanced disease that requires combined treatment approaches, including surgery, radiation, and chemotherapy. For HPV-positive HNSCC, the prognosis following these treatment modalities is favorable; however, for HPV-negative HNSCC, half of patients will relapse within 2 years. For patients with relapsed disease, targeting the programmed cell death 1 receptor (PD-1) with the antibody pembrolizumab is currently approved as first-line treatment. Although pembrolizumab can lead to durable responses, overall response rates are low and novel therapies that aim to improve the clinical outcome of patients with anti-PD-1 refractory or relapsed HNSCC are needed. Our laboratory and others have previously demonstrated a role for the chemokine interleukin-8 (IL-8, CXCL8) in mechanisms of tumor progression in several tumor types, including as a driver of resistance to chemotherapy, EGFR-targeted therapy, and immunotherapy. IL-8 is a chemokine of the CXCL family that binds to two receptors, CXCR1 and CXCR2, expressed on myeloid cells, endothelium, and cancer cells. In addition, CXCR1/2 bind six other redundant chemokines of the same family, CXCL1/2/3/5/6/7. IL-8 in particular has been shown to facilitate the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) to the tumor microenvironment (TME) while also driving tumor cell plasticity in the context of an epithelial-mesenchymal transition (EMT) leading to increased tumor cell migration, invasiveness, and resistance to cell death. We have now characterized the link between CXCR1/2 signaling and response to chemotherapy in HNSCC. Analysis of HNSCC tissues shown that IL-8 and the CXCR1/2 receptors are expressed at higher levels in tumors compared with normal tissues. Furthermore, analysis of patient data in The Cancer Genome Atlas (TCGA) database and characterization of various HNSCC cell line models revealed that expression of IL-8 and CXCR1/2 receptors are significantly higher in HPV-negative HNSCC compared with HPV-positive cases. Inhibition of CXCR1 and CXCR2 signaling via SX-682, a small molecule inhibitor currently under evaluation in the clinic, allowed several human and murine HPV-negative HNSCC models to be sensitized to the cytotoxic activity of docetaxel in vitro and in vivo. This phenomenon was associated with a decrease of tubulin beta-3, a protein involved in conferring resistance to microtubule-targeting chemotherapies. Modulation of the immune compartment in a syngeneic murine model of HPV-negative HNSCC was also observed following combined treatment with docetaxel and SX-682, providing rationale for future combination studies with immune-based therapies. The results of these investigations are being translated into a clinical study that is currently in the review phase at the NIH Clinical Center.