PROJECT SUMMARY Human papillomaviruses (HPVs) are causally linked to 5% of all human cancers, including nearly all cervical cancers and ~25% of head and neck squamous cell carcinomas (HNSCCs), largely driving an ongoing epidemic increase of HPV-positive (HPV+) HNSCCs over recent decades. However, little is known about the mechanisms of disease progression driven by HPV, particularly in the context of host immunity. Based on our preliminary findings, we will study the mechanism by which the chemokine CXCL14 suppresses HNSCC growth, and test if CXCL14 serves as a useful immunomodulatory target for novel immunotherapies to treat HPV+ HNSCC. Recently, we have revealed that restoring the suppressed expression of CXCL14 in HPV+ HNSCC cells greatly suppressed tumor growth in immunocompetent syngeneic mice through upregulation of MHC-I antigen presentation and antigen-specific CD8+ T cells responses. Based on our findings, we hypothesize that CXCL14 induces antitumor immune responses that suppress HPV+ HNSCC by enhancing antigen presentation and eliciting CD8+ T cell responses, and thus CXCL14 is a potential novel immunotherapeutic agent. To test our hypothesis, we will 1) Define the mechanisms by which CXCL14 upregulates MHC-I antigen presentation to mediate tumor suppression; 2) Define the mechanisms by which CXCL14 induces CD8+ T cell infiltration/activation and tumor suppression; and 3) Test CXCL14-based immunotherapies that induce antitumor immunity and clear HPV+ HNSCC. Our study will provide new mechanistic understanding of antitumor immune defenses in HPV+ HNSCC and may lead to a novel immunotherapy for HNSCC, particularly for the non- responders in current immunotherapies.