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.
Poudel et al. (Wed,) studied this question.