Other extrinsic factors that have been described include T-cell related factors (alternative immune checkpoints, T-cell exhaustion and phenotype alteration, T-cell receptor (TCR) repertoire, and epigenetic modification), cytokines and metabolites (e.g., TGF-B, adenosine) related to the tumour micro-environment [21,61,62]. This evidence concerns the gene TGFB1 and neoplasm.