Fig. 4

Negative effect of ITH in MSI tumor under immunotherapy. a In MSI tumors, hyperactivation of WNT/β-catenin signaling suppresses effector T cells function by reducing IFN-γ. Mutations in JAK and STAT result in impaired IFN-γ signaling and lack of induced MHC class I expression. Moreover, JAK1/2 controls chemoattractant such as CXCL9, CXCL10 and CXCL11, and mutations in JAK1/2 cause lack of downstream T cell infiltration. β2M gene mutations lead to impaired MHC class I function and knockdown of INCR1 decreases PD-L1 expression. Dysfunction of IFN-γ signaling results in lack of PD-L1 expression which leads to PD-L1 blockade out of target, and defective migration of adoptive T cells into tumors in melanoma thereby reducing the efficacy of ICB. b Appropriate level of neoantigen ITH leads to adequate TCR expansion, sufficient infiltration and high TCR affinity, which lead to cytotoxic effects of immunotherapy. In the other hand, excessive expression of neoantigen ITH leads to inadequate TCR expansion, insufficient infiltration and T cell exhaustion, which result in inefficient immunotherapy