Author ORCID Identifier
https://orcid.org/0000-0002-5550-5589
Date of Graduation
5-2018
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Dr. Michael A. Curran, Ph.D.
Committee Member
Dr. James P. Allison, Ph.D.
Committee Member
Dr. Willem Overwijk, Ph.D.
Committee Member
Dr. Gregory Lizee, Ph.D.
Committee Member
Dr. Michael Davies, M.D., Ph.D
Abstract
Tumor immunotherapy has shown very promising clinical benefit across an array of cancers; however, two major challenges remain unresolved in the field. First, many patients do not respond to therapy at all or relapse after a period of remission. Second, there are often dose-limiting immune related adverse effects associated with immunomodulation.
In order to understand the mechanisms employed by tumors to evade immunotherapeutic responses, we established a murine model of melanoma designed to elucidate the molecular mechanisms underlying immunotherapy resistance. Through multiple in vivo passages, we selected a B16 melanoma tumor line that evolved complete resistance to combination blockade of CTLA-4, PD-1, and PD-L1, which cures ~80% of mice bearing the parental tumor. Using gene expression analysis, and immunogenomics, we determined the adaptations engaged by this melanoma to become completely resistant to triple combination T cell checkpoint blockade. Acquisition of immunotherapy resistance by these melanomas was driven by the coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways to create a metabolically hostile microenvironment wherein T cell functions are suppressed. Together these data indicate that by adapting a hyper-metabolic phenotype, melanoma tumors can achieve resistance to T cell checkpoint blockade allowing them to escape host immune control.
Increasing the potency of antitumor immunity with immunotherapy disrupts the tightly controlled state of immunologic homeostasis in the body which can lead to reactivation of peripherally-tolerized T cell responses with the potential to mediate uninvited toxicities. Agonist antibodies targeting the T cell co-stimulatory receptor 4-1BB (CD137) are among the most effective immunotherapeutic agents across pre-clinical cancer models. Clinical development of these agents, however, has been hampered by dose-limiting liver toxicity. Lack of knowledge of the mechanisms underlying this toxicity has limited the potential to separate 4-1BB agonist driven tumor immunity from hepatotoxicity. The capacity of 4-1BB agonist antibodies to induce liver toxicity was investigated in wild type and genetically-modified immunocompetent mice. We find that activation of 4-1BB on liver myeloid cells is essential to initiate hepatitis. Once activated, these cells produce interleukin-27 that is required for liver toxicity. CD8 T cells infiltrate the liver in response to this myeloid activation and mediate tissue damage. Co-administration of CTLA-4 and/or CCR2 blockade may minimize hepatitis, but yield equal or greater antitumor immunity.
Keywords
Immunotherapy Resistance, Immunooncology, CTLA-4, PD-1, PD-L1, 4-1BB, Immune Related Adverse Effects (IRAEs), Immunometabolism, Checkpoint Blockade Immunotherapy, Hepatotoxicity
Included in
Genetic Processes Commons, Immunity Commons, Immunopathology Commons, Immunoprophylaxis and Therapy Commons, Medical Biochemistry Commons, Medical Biotechnology Commons, Medical Genetics Commons, Medical Immunology Commons