Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Immunobiology
First Advisor
Craft, Joseph
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for ~1.8 million deaths annually. Lung adenocarcinoma (LUAD) is the most common form of non-small cell lung cancer (NSCLC; 40% of cases) and is most frequently associated with mutations in KRAS proto-oncogene (30% of cases). Traditionally, therapeutic options for KRAS-mutant LUAD have been limited, but the successful application of immune checkpoint blockade (ICB) targeting the PD-1 pathway has changed the therapeutic landscape. The success of PD-1-blockade therapy has also changed the perception that LUAD is a non-immunogenic cancer type because anti-PD-1/PD-L1 treatment potentiates the function of previously activated T cells, suggesting that therapy-responsive LUAD patients had potent, ongoing anti-tumor immune responses at the time of therapy administration. However, only ~20% of LUAD patients benefit from ICB and improving response rates will require a better understanding of the anti-tumor immune response, including how different types of tumor-infiltrating T cells interact with other immune cells and contribute to anti-tumor immunity. CD4 T cell and B cell interactions are necessary for the proper development and function of T follicular helper (TFH) cells and germinal center (GC) B cells in infection, vaccine responses, and autoimmune diseases. In various types of human cancers, the presence of B cells and TFH cells is correlated with prolonged survival and favorable therapeutic responses. This correlation is especially strong when B cells and TFH cells are in tumor-associated tertiary lymphoid structures (TLSs) with highly-organized follicles and germinal centers. Yet, the functional significance and cellular mechanisms of TFH and B cell collaborations in cancer have not been well characterized before. Herein, I present an introduction to B cell and CD4 T cell collaboration in tumor-associated lymphoid tissues, i.e., tumor-draining lymph nodes (LNs) and TLSs, and how this collaboration affects CD8 T cell differentiation and function. In Chapter 1, I describe the modalities for investigating tumor-specific T and B cell responses, with a focus on the development of antigen-programmed LUAD murine models. In Chapter 2, I characterize how B cell and CD4 T cell collaboration augments anti-tumor immunity. In Chapter 3, I discuss the shared differentiation pathways with B cell-TFH cell-IL21 axis under the context of chronic viral infection and cancer, and future directions on the therapeutic potential of these pathways. Together, my research has highlighted the essential role of tumor-specific TFH and B cell collaboration in evoking protective immune responses against cancer and explored one of the mechanisms where T-B-interaction-dependent IL-21 production promotes CD8 T cell effector functions. We have established several novel platforms where LUAD tumors express T cell and B cell neoantigens, which enables further studies on interactions between B cells and CD4 T cells in tumor-associated lymphoid tissues. These findings suggested that therapeutic designs leveraging the B cell-TFH cell-IL21 axis could advance existing immunotherapies and improve response rates for patients with lung and other cancers.
Recommended Citation
Cui, Can, "Neoantigen-driven B cell and CD4 T cell Collaboration Promotes Anti-tumor CD8 T Cell Responses in Lung Adenocarcinoma" (2022). Yale Graduate School of Arts and Sciences Dissertations. 759.
https://elischolar.library.yale.edu/gsas_dissertations/759
