Date of Award
8-14-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The immune system plays an essential role in cancer evolution and cancer treatment. One of the major mechanisms of immune-mediated tumor rejection is the recognition of tumor antigens by T cells. Upon recognition of tumor antigens, naïve T cells become activated and subsequently infiltrate inside the tumor. Since the early discovery of tumor-specific T cells, many efforts have elucidated the molecular nature of their cognate antigens. It is now established that MHC-I and MHC-II restricted peptides are critical to generate CD8+ and CD4+ antigen-specific T cells that can recognize tumor-derived antigens. Two main categories of these antigens are those originating from normal protein sequences (self-antigens) and those produced from protein alterations (neoantigens). Historically, efforts targeting self-antigens dominated the field, due to challenges in detecting neoantigens. However, self-antigen targeting therapies have largely produced minimal clinical benefits, questioning their relevance for cancer immunotherapy. Recent technical advances in genomics, computational algorithms, and proteomics made it possible to identify neoantigens. As the field shifting towards neoantigen targeting therapies, it remains unclear whether neoantigens are better than self-antigens in terms of mediating tumor rejections, and whether T cell responses against neoantigens and self-antigens are interrelated or not. Head-to-head comparison of a neoantigen and a self-antigen is needed to address these questions. Mass spectrometry (MS)-based antigen identification is a method that can detect both neoantigens and self-antigens from the tumor immunopeptidomes. It has the advantage of being a direct identification method but often suffers from detection sensitivity issues. Here, we established an MS pipeline that allowed us to examine both neoantigens and self-antigens using mouse sarcoma models generated in the lab. We first demonstrated the identification of a list of immunologically validated, therapeutically relevant neoantigens by MS. We then developed novel MS methods that significantly improved the detection sensitivity, achieving detection of major MHC-I neoantigens at single tumor level. Meanwhile, by comparing immunopeptidomes across immunologically distinct sarcoma cell lines and normal cells, we screened a list of self-peptides and identified one candidate as a potential self-antigen. Overexpression of this self-peptide enhanced tumor immunogenicity in various tumor models, both during primary tumor challenge and in memory rechallenge settings. Intriguingly, we observed that a concomitant expression of at least one neoantigen is required for this self-peptide to mediate its anti-tumor responses. This indicates that neoantigens may be acting as adjuvants to self-antigens, likely through epitope spreading. Together, we demonstrated the utility of MS-based antigen discovery approaches and yielded improved MS methods for tumor antigen detection. We also shed light on the interrelationship between neoantigens and self-antigens. Our data suggested that a T cell response against neoantigens may be a prerequisite to elicit T cell responses to self-antigens. These will have clinical implications in designing optimal T cell-based cancer immunotherapies.
Language
English (en)
Chair and Committee
Robert Schreiber
Recommended Citation
Meng, Wei, "Mass Spectrometry-Based Discovery of Tumor Antigens for Cancer Immunotherapy" (2023). Arts & Sciences Electronic Theses and Dissertations. 3137.
https://openscholarship.wustl.edu/art_sci_etds/3137