Tumor Immunotherapy: Mechanisms of Acquired Resistance and Characterization of Immune Related to xicities

<p>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.</p> <p>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.</p> <p>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2018

Authors dc:creator

• Jaiswal, Ashvin
• <p>https://orcid.org/0000-0002-5550-5589</p>

Contributors dc:contributor

• Dr. Michael A. Curran, Ph.D.
• Dr. James P. Allison, Ph.D.
• Dr. Willem Overwijk, Ph.D.

• Immunotherapy Resistance
• Immunooncology
• CTLA-4
• PD-1
• PD-L1
• 4-1BB
• Immune Related Adverse Effects (IRAEs)
• Immunometabolism
• Checkpoint Blockade Immunotherapy
• Hepatotoxicity
• Genetic Processes
• Immunity
• Immunology and Infectious Disease
• Immunopathology
• Immunoprophylaxis and Therapy
• Medical Biochemistry
• Medical Biotechnology
• Medical Genetics
• Medical Immunology
• Medicine and Health Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/832

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1877