Mechanisms of Acquired Resistance to Immune Therapies in Lung Cancer
Date of Award
Doctor of Philosophy (PhD)
Despite the widespread use of immune checkpoint inhibitors in the treatment of lung and other cancers, only a minority of patients benefit from treatment and approximately 50% develop acquired resistance. The underlying mechanisms that drive tumor escape remain poorly understood yet are essential to inform strategies that can delay or overcome resistance. In Chapters 2 and 3, we investigated the mechanisms that drive resistance to immune checkpoint inhibitors (ICIs) in mouse models of lung cancer, with a focus on the basic biology of tumor-immune interactions and how these interactions are modified by therapy. In Chapter 2, we investigated the genomic, transcriptional, and functional features of Msh2 deficient lung tumors that initially responded but eventually developed acquired resistance to treatment with either anti-PD-1 alone or the combination of anti-PD-1 plus anti-CTLA-4. We identified tumor hypoxia as a dominant feature of resistant tumors, and targeting hypoxic tumor regions with TH-302, a hypoxia-activated cytotoxic agent, delayed the emergence of acquired resistance to ICIs. Thus by investigating novel mediators of acquired resistance, our work suggests that hypoxia may be a relevant target to increase the durability of responses to ICIs in lung cancer. In Chapter 3, we employed mass spectrometry approaches to directly identify and compare the nature and abundance of tumor neoantigens in both ICI-sensitive and resistant tumor cells, providing additional insights into the role that tumor neoantigen loss plays in the development of resistance, which has been challenging to study in patient samples. We found that ICI-resistant tumor cells had a profound loss neoantigen peptides presented by MHC-I, but not MHC-II, emphasizing the importance of tumor neoantigen-specific CD8+ T cells in mediating responses to ICI therapy. In a separate study presented in Chapter 4, we also investigated murine EGFR mutant lung cancers that exhibited primary resistance to ICIs. Although our initial goal was to investigate alternative strategies of immune modulation with a focus on regulatory T cells, we instead made the unexpected discovery that systemic administration of diphtheria toxin induced rapid and reversible tumor regression in this genetically engineered model. This work demonstrates that the potential of bacterial agents to induce anti-tumor responses can be mediated through direct cytotoxic effects and highlights a unique vulnerability of EGFR-mutant lung cancers. Collectively, the work presented here adds to our understanding of the therapeutic vulnerabilities of lung tumors and suggests strategies to combat resistance to immune based therapies in the clinic.
Robles-Oteiza, Camila, "Mechanisms of Acquired Resistance to Immune Therapies in Lung Cancer" (2021). Yale Graduate School of Arts and Sciences Dissertations. 400.