Neoantigens and Stochastic Fluctuations Regulate T Cell Proliferation in Primary and Metastatic Malignant Brain Tumors

Brain cancer is one of the most aggressive forms of cancer in the central nervous system occurring as primary or metastatic tumors. Sequencing of resected tissues from glioblastoma (GBM) and brain metastases (BrMET) reveals high heterogeneity in neoantigens and T cell receptor (TCR) repertoires. Our analysis of published sequencing data in different spatial regions of tumors GBM and BrMET patients show the presence of T cell clones of sizes with a heavy right-tailed distribution spanning several orders of magnitude (e.g., 1 - 1000 cells) with a few (<10) large clone sizes and many small clones. We investigated how neoantigens in the tumor microenvironment (TME) drive T cell expansion in GBM and BrMET by developing a mechanistic mathematical model based on the interaction of T cells and the neoantigens that incorporates their stochastic proliferation in the immunosuppressive environment and trained it to predict the emergence of T cell clones in different spatial regions. The model accurately predicts the distribution of observed T cell clone sizes and reveals that the strength of interaction between TCR and neoantigen-MHC complex and stochastic T cell proliferation crucially regulates T cell expansion in the TME. It also suggests higher rate of T cell proliferation BrMET compared to GBM. An extended version of the model predicts the ability of individual neoantigens to generate T cell clones in the periphery in patients receiving personalized neoantigen vaccines. Our model may facilitate the discovery of improved peptide combinations in neoantigen vaccine studies. Significance StatementNeoantigen-driven T cell responses are key to immune defense against solid tumors. Multi-region sequencing of brain tumors reveals spatial heterogeneity in neoantigens and T cell repertoires. To understand whether neoantigen-driven T cell expansion underlies the TCR repertoire heterogeneities, we developed a stochastic, mechanistic model of T cell proliferation using published TCR and neoantigen data from primary and metastatic brain tumors. The model accurately predicts clone size distributions, showing faster T cell proliferation in metastases and stronger responses to clonal (shared) neoantigens than to private (region-specific) ones. The model is extended to describe T cell clonal expansion in the periphery in response to neoantigen vaccine in glioblastoma patients. This framework may help design optimal peptide combinations in neoantigen vaccine development.