Neoantigens and stochastic fluctuations regulate T cell proliferation in primary and metastatic malignant brain...

Brain cancer can occur as primary or metastatic tumours. Sequencing of resected tissues from primary glioblastoma (GBM) and brain metastases (BrMET) reveals high heterogeneity in neoantigens and T cell receptor (TCR) repertoires. Analysis of published sequencing data from different spatial regions of tumours in GBM and BrMET patients reveals a heavy right-tailed distribution of T cell clone sizes, spanning several orders of magnitude (1-1000 cells), with a few large clone sizes (less than 10) and many small clones. We developed a mathematical model that incorporates the interaction of T cells and neoantigens, taking into account their stochastic proliferation within the immunosuppressive tumour microenvironment, to investigate how neoantigens drive T cell expansion in GBM and BrMET. The model trained to describe the emergence of T cell clones in different spatial regions accurately predicts the distribution of observed T cell clone sizes. The model reveals that the strength of interaction between TCR and neoantigen-major histocompatibility complex and stochastic T cell proliferation crucially regulates T cell expansion and suggests a higher rate of T cell proliferation in BrMET compared with GBM. An extension of the model predicts peripheral T cell responses to neoantigen vaccines, potentially aiding optimal peptide selection.