Author ORCID Identifier
0000-0002-7395-9939
Date of Graduation
12-2017
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
P. Andrew Futreal, Ph.D.
Committee Member
James P. Allison, Ph.D.
Committee Member
Giulio Draetta, M.D., Ph.D.
Committee Member
Patrick Hwu, M.D.
Committee Member
Greg Lizee, Ph.D.
Committee Member
Nicholas Navin, Ph.D.
Committee Member
Paul A. Scheet, Ph.D.
Abstract
Melanoma is the most malignant form of skin cancer. The five-year survival rate for metastatic melanoma is 19.9%. Although targeted therapy of BRAF and MEK inhibitors were developed for melanoma, resistance to therapy is inevitable. Immune checkpoint blockade, which reverses the suppression of the immune system, on the other hand, has shown a durable response in 20-30% of patients with metastatic melanoma. However, more predictive and robust biomarkers of response to this therapy are still needed, and resistance mechanisms remain incompletely understood. To address this, we examined a cohort of metastatic melanoma patients treated with sequential checkpoint blockade against cytotoxic T lymphocyte antigen–4 (CTLA-4) followed by programmed death receptor–1 (PD-1) by immunogenomic profile analyses from serial tumor biopsies.
From immune profiling (12 marker immunohistochemistry and NanoString Gene Expression Profiling), we found that adaptive immune signatures in tumor biopsies obtained from early on-treatment time points are predictive of response to immune checkpoint blockade. We also demonstrated differential mechanistic signatures of tumor microenvironment induced by CTLA-4 and PD-1 blockade. Importantly, VEGFA was identified as a potential target of combination therapy withPD-1blockade.
From genomic profiling (whole exome sequencing and T cell receptor sequencing), we demonstrated that a higher TCR clonality in pre-treatment biopsy was predictive of response to PD-1 but notCTLA-4blockade. We also observed increased TCR clonality after CTLA-4 blockade treatment in patients responding to the following PD-1 blockade treatment. Analysis of copy number alterations (CNAs) identified a higher burden of copy number loss in nonresponders to CTLA-4 and PD-1 blockade and found that it was associated with decreased expression of genes in immune-related pathways. The effect of mutational load and burden of copy number loss on response was nonredundant, suggesting the potential utility of these as a combinatorial biomarker to optimize patient care with checkpoint blockade therapy.
In summary, our integrative cancer immunogenomic analysis shows that genomic and immune profiling of longitudinal tumor biopsies can identify novel biomarkers and resistance mechanisms of immune checkpoint blockade.
Keywords
cancer immunology, immunotherapy, immune checkpoint blockade, CTLA-4, PD-1, genomics, melanoma, response, resistance, biomarker
Included in
Bioinformatics Commons, Computational Biology Commons, Genomics Commons, Medical Immunology Commons, Skin and Connective Tissue Diseases Commons