Determinants of Adaptive Immunity in Cancer
Immune checkpoint blockade results in T cell antitumor responses but most patients fail to respond. This raises fundamental questions about mechanisms of tumor immune recognition and resistance. Here, I first report tumor regressions in a subset of patients with metastatic melanoma treated with anti-CTLA4 antibody and radiation (RT) and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumors, resistance was common due to upregulation of PD-L1 on tumor cells and corresponding T cell exhaustion. Accordingly, optimal response in melanoma and other cancer types required RT, anti-CTLA4, and anti-PD-L1/PD1. When I investigated determinants of improved responses to combination therapy, I found that RT enhanced the antigenic diversity of intratumoral T cells, anti-CTLA4 predominantly inhibited regulatory T cells, and anti-PD-L1 reversed T cell exhaustion. I next extended my investigation of this combination therapy to pancreatic ductal adenocarcinoma (PDA), finding that optimal responses required addition of agonist CD40 monoclonal antibody. To further understand determinants of response and resistance in PDA, I next examined the immune landscape of PDA in humans. I report that human PDA displays a range of intratumoral cytolytic T cell activity: PDA tumors with low cytolytic activity exhibited significantly increased copy number alterations, high cytolytic activity in PDA did not correlate with increased neoepitope load, and PDA tumors exhibited a unique pattern of immune suppressive molecule expression. To place PDA in a wider context of human adaptive antitumor immunity, I then extended this analysis to 35 solid tumor types, finding abundant neoepitopes across human cancer at the global level and identifying immune gene sets predictive of neoepitope load. Overall, distinct rates of neoepitope generation, cytolytic activity, and immune suppressive molecule expression define disease types across human cancer. In summary, these findings characterize mechanisms of response and resistance to immune checkpoint blockade in distinct tumor types and investigate determinants of adaptive immunity in human cancer.
Rech, Andrew J, "Determinants of Adaptive Immunity in Cancer" (2017). Dissertations available from ProQuest. AAI10256375.