Investigating the mechanism of K17-mediated immunosuppression in papillomavirus-induced cancers - PROJECT SUMMARY/ABSTRACT My long-term career goal is to become an independent scientist in an academic research institution. My research interest focuses on investigating novel molecular mechanisms underlying immunosuppression in tumor microenvironment to provide new therapeutic targets and approaches to improve cancer immunotherapy treatments. The proposed studies for the K22 award will form the foundation for my future research as I transit from a researcher to a junior faculty member. High risk human papillomaviruses (HPV) cause 5% of all human cancers, including majority of cervical cancer, anal cancer, skin cancer and a growing fraction of oropharyngeal cancer. We have used mouse papillomavirus (MmuPV1), a virus thought to model HPV infection in laboratory mice, to study host factors that contribute to persistent viral infection, a risk factor for tumor progression to cancer in papillomavirus-induced neoplastic diseases. We have identified stress keratin 17 (K17) as a critical host factor exploited by MmuPV1 to establish persistent infection. The same mechanism is used in HPV negative head and neck cancers in mice and in humans to modulate tumor immune microenvironment and mediate resistance to immune checkpoint blockade (ICB) therapy. The goal of this proposal is to reveal the molecular mechanisms underlying K17-mediated immune suppression using MmuPV1 as an infection-induced neoplastic disease model. Based upon what we have learned so far from my postdoctoral studies, we hypothesize that K17 functions through downregulating tumor cell MHC class II expression, and polarizing macrophages in the tumor microenvironment to prevent T cell infiltration. I propose the following aims:1) define the role of immune cell subsets, especially CXCL9-producing macrophages, in K17-mediated immune evasion in the context of papillomavirus-induced disease; 2) determine tumor cell-intrinsic mechanisms associated with K17 expression that contribute to immune evasion. In Aim1, I propose to test the importance of macrophages in K17-mediated immune suppression by characterizing the macrophage subsets comprehensively through phenotyping and in vivo functional transfer studies. In this aim, I will continue to collaborate with Dr. Huy Dinh, a computational biologist with a research interest in tumor immunology, to systemically study other immune cell subsets and tumor-immune cell-cell interactions that may play a role in K17-mediated immune suppression. In Aim2, I propose to study the tumor cell intrinsic mechanisms regulated by K17 expression, with a focus on MHC class II expression. Our preliminary data showed an inverse correlation between tumor cell K17 expression and tumor cell-intrinsic MHC class II expression. In this aim, I will collaborate with Dr. Huy Dinh on spatial transcriptomic studies to further investigate how MHC class II expression regulated by K17 affect immune landscape in tumors. What I learned from proposed studies may have broad impact on many other epithelial-originated cancers where K17 is overexpressed.
