Liver disease impact on myeloid cells driving immunotherapy resistance in hepatocellular carcinoma - Project Summary/Abstract Recent advances in the treatment of hepatocellular carcinoma (HCC) with immunotherapy have improved therapeutic options for patients living with this cancer; however, many patients still do not benefit, and response to immunotherapy regimens is complicated by underlying liver disease which exists simultaneously with HCC. Dr. Keenan has designed and analyzed experiments uncovering mechanisms of resistance to immunotherapy using single cell techniques in another primary liver cancer, specifically a population of immunosuppressive myeloid cells (“CD14CTX”) that can induce immune paralysis in T cells. Her hypotheses are that CD14CTX suppressive myeloid cells are enriched within non-virally-associated HCC, and that tyrosine kinase inhibitors (TKI) which modulate myeloid cells can inhibit the suppressive functions of myeloid cells when given in combination with checkpoint inhibitors (CPI). In Aim 1, she will use previously validated high- dimensional single cell and in vitro assays to examine CD14CTX in viral and non-viral hepatitis. In Aim 2, she will use spatial transcriptomics/proteomics and in vivo models to decipher spatial relationships within HCC tumors by liver disease etiology. Finally in Aim 3, she will investigate the impact of CPI and TKI on myeloid cell suppressive function using longitudinal patient samples and mechanistic assays. Dr. Keenan has outlined a five-year career development plan to help her to achieve an independent lab-based research career as an expert in liver immunobiology and cancer immunotherapy. To meet this goal, she has formed an Advisory Committee of mentors with expertise in hepatobiliary malignancies and liver disease, single cell techniques and computational immunology, and cancer immunotherapy, as well as abundant experience mentoring other early career physician scientists. She has also assembled collaborators to provide their expertise in liver immunobiology and tumor immunology, biostatistics, and single cell RNA and TCR sequencing analysis. Dr. Keenan’s training plan objectives are to gain expertise in: 1) liver disease biology, 2) spatial transcriptomics and proteomics, 3) translation to clinical trials. These will be accomplished through hands-on tutorials with members of her advisory committee and collaborators, and from didactic courses in her protected time provided by this training award. At the completion of this award, Dr. Keenan will have made substantial progress to advance the field of cancer immunotherapy for patients with hepatocellular carcinoma and towards her career development as a leader in the field of cancer immunology translational research.
