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Principal Investigator: Wei Wang
Organization: HENRY FORD HEALTH + MICHIGAN STATE UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $193,616
Funding agency: National Cancer Institute
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.
Terms: <Affect><Anal Cancer><Anal Cancers><Anus Cancer><Breast Cancer><CD183><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CKR-L2><CMKAR3><CRG-2><CXCL10><CXCL10 gene><CXCL9><CXCL9 gene><CXCR3><CXCR3 gene><Cancer Induction><Cancer Model><Cancer Patient><CancerModel><Cancers><Carcinoma><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Lineage><Cell Signaling><Cell-to-Cell Interaction><Cells><Cervical Cancer><Cervix Cancer><Chemokine (C-X-C Motif) Receptor 3><Chemotactic Cytokines><Class II Genes><Collaborations><Data><Disease><Disorder><Down-Regulation><Epithelial Cells><Epithelial cancer><Epithelium><Faculty><Foundations><Future><G Protein-Coupled Receptor 9><GPR9><Genes><Goals><HLA Class II Genes><HNC patient><HPV><HPV associated HNSCC><HPV driven HNSCC><HPV driven head and neck cancer><HPV induced cancer><HPV infection><HPV malignancy><HPV(+) HNSCC><HPV(+) head and neck squamous cell carcinoma><HPV(-) HNSCC><HPV(-) head and neck squamous cell carcinoma><HPV+ HNSCC><HPV+ cancer><HPV+ head and neck cancers><HPV- HNSCC><HPV-Related Malignancy><HPV-associated cancer><HPV-associated head and neck cancer><HPV-associated head and neck squamous cell carcinoma><HPV-associated malignancy><HPV-negative HNSCC><HPV-negative head and neck cancer><HPV-negative head and neck squamous cell carcinoma><HPV-positive HNSCC><HPV-positive head and neck cancers><HPV-related HNSCC><HPV-related cancer><HPV-related head and neck squamous cell carcinoma><Homologous Chemotactic Cytokines><Host Factor><Host Factor Protein><Human><Human Papilloma Virus><Human Papilloma Virus-Related Malignancy><Human Papilloma Virus-Related Malignant Neoplasm><Human Papilloma Virus-associated cancer><Human Papilloma Virus-associated malignancy><Human Papilloma Virus-related cancer><Human Papillomavirus><Human papilloma virus infection><Human papillomavirus cancer><Human papillomavirus driven HNSCC><Human papillomavirus driven head and neck cancer><Human papillomavirus induced cancer><Human papillomavirus infection><Human papillomavirus malignancy><Human papillomavirus-Related Malignancy><Human papillomavirus-Related Malignant Neoplasm><Humig><IFI10><INP10><IP-10><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><Immune><Immune Evasion><Immune infiltrates><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Impairment><Infection><Infectious Human Wart Virus><Infiltration><Institution><Integration Host Factors><Intercrines><Intermediate Filaments><Intracellular Communication and Signaling><Investigators><K22 Award><Keratin><Laboratory mice><Learning><Lesion><Lymphoid><MHC Class II><MHC Class II Genes><MIG Gene><MOB-1><Macrophage><Malignant Anal Neoplasm><Malignant Anal Tumor><Malignant Breast Neoplasm><Malignant Cell><Malignant Cervical Neoplasm><Malignant Cervical Tumor><Malignant Epithelial Neoplasms><Malignant Epithelial Tumors><Malignant Melanoma><Malignant Neoplasm of the Cervix><Malignant Neoplasms><Malignant Oropharyngeal Neoplasm><Malignant Oropharyngeal Tumor><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Pancreatic Neoplasm><Malignant Skin Neoplasm><Malignant Tumor><Malignant Tumor of the Anus><Malignant Tumor of the Cervix><Malignant Tumor of the Cervix Uteri><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant Uterine Cervix Neoplasm><Malignant Uterine Cervix Tumor><Malignant neoplasm of anus><Malignant neoplasm of cervix uteri><Malignant neoplasm of lung><Malignant neoplasm of ovary><Malignant neoplasm of pancreas><Mediating><Melanoma><Mice><Mice Mammals><Mig Receptor><Mig-R><MigR><Modeling><Modern Man><Molecular><Murine><Mus><Myelogenous><Myeloid><Mφ><Oncogenic><Oropharnyx Cancers><Oropharyngeal Cancer><Oropharyngeal Carcinoma><Oropharynx Cancer><Oropharynx Carcinoma><Ovary Cancer><Pancreas Cancer><Pancreatic Cancer><Papilloma Viruses><Papillomaviridae><Papillomavirus><Papillomavirus Infections><Patients><Phenotype><Play><Postdoc><Postdoctoral Fellow><Production><Prognosis><Proteins><Public Health><Publishing><Pulmonary Cancer><Pulmonary malignant Neoplasm><Regulation><Reporting><Research><Research Associate><Research Personnel><Research Proposals><Researchers><Resistance><Risk Factors><Role><SCYB10><SCYB9><SIS cytokines><Sampling><Scientist><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Skin Cancer><Stress><T cell infiltration><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TCGA><Technology><Testing><The Cancer Genome Atlas><Tissue Arrays><Tissue Chip><Tissue Microarray><Transgenic Mice><Tumor Cell><Tumor-infiltrating immune cells><Uterine Cervix Cancer><Viral Diseases><Virus><Virus Diseases><Work><anal squamous cell carcinoma><anti-cancer immunotherapy><anticancer immunotherapy><biological signal transduction><cancer cell><cancer immunology><cancer immunotherapy><cancer infiltrating T cells><cancer microenvironment><cancer progression><cancer type><carcinogenesis><career><check point blockade><checkpoint blockade><chemoattractant cytokine><chemokine><chronic infection><crg-10><disease model><disorder model><epithelial carcinoma><gIP-10><head and neck cancer patient><high risk><host response><human papilloma virus+ head and neck squamous cell carcinoma><human papillomavirus (-) head and neck squamous cell carcinoma><human papillomavirus - head and neck squamous cell carcinoma><human papillomavirus associated head and neck cancer><human papillomavirus associated head and neck squamous cell carcinoma><human papillomavirus associated malignancy><human papillomavirus driven head and neck squamous cell carcinoma><human papillomavirus induced head and neck squamous cell carcinoma><human papillomavirus negative head and neck cancer><human papillomavirus negative head and neck squamous cell carcinoma><human papillomavirus positive HNSCC><human papillomavirus positive head and neck cancers><human papillomavirus positive head and neck squamous cell carcinoma><human papillomavirus related head and neck squamous cell carcinoma><human papillomavirus- head and neck squamous cell carcinoma><human papillomavirus-associated cancer><human papillomavirus-related cancer><immune cell infiltrate><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point blockade><immune checkpoint blockade><immune evasive><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunological status><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><in vivo><infiltration of tumors by immune cells><insight><interest><intratumoral immune cell><intratumoral immune infiltrate><keratinocyte><lung cancer><malignancy><malignant breast tumor><malignant oropharynx neoplasm><malignant oropharynx tumor><malignant skin tumor><member><neoplasm immunology><neoplasm progression><neoplasm/cancer><neoplastic><neoplastic cell><neoplastic progression><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><non-HPV HNSCC><non-human papillomavirus head and neck squamous cell carcinoma><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><oral HPV-positive HNSCC><oral HPV-positive head and neck cancers><oral human papillomavirus positive head and neck cancers><oral human papillomavirus positive head and neck squamous cell carcinoma><ovarian cancer><overexpress><overexpression><pancreatic malignancy><papilloma virus Infections><persistent infection><post-doc><post-doctoral><post-doctoral trainee><prevent><preventing><research associates><resistant><response><social role><thymus derived lymphocyte><transcriptomics><tumor><tumor immune cell><tumor immune infiltrate><tumor immune microenvironment><tumor immunology><tumor infiltrating T cells><tumor infiltration of immune cells><tumor microenvironment><tumor progression><tumor-immune system interactions><viral infection><virus infection><virus-induced disease><wart virus>