FIGURE 2.

Mechanisms of primary resistance. (a) Tumors with high mutation burden are more likely to respond to anti-PD1/PDL1 therapy because there is a greater possibility of generating immunogenic neoantigens which activate CD8⁺ T cells and induce tumor rejection reactivity. (b) Tumor cells with primary B2M mutation fail to present tumor antigens and elicit antitumor immunity which is required for tumor cell killing. (c) Tumor cells resistant to IFN-γ signaling because of primary JAK1/2 mutation can not induce PDL1 upregulation but inhibit T cell reactivity in PD1/PDL1 independent pathway. The inactivation of IFN-γ signaling also downregulates CXCL9 and CXCL10 expressions which are necessary for T cell trafficking. (d) Alternative immune checkpoints are upregulated in tumor infiltrating T cells, and thus only blocking PD1/PDL1 axis is not enough to rescue the severely exhausted T cells. Upregulation of VEGFR signaling and TOX expression aggravates the activation of inhibitory signaling. (e) TME contains diverse immunosuppressive cells that influence anti-PD1/PDL1 efficacy through inhibiting T cell reactivity. Cytokines derived from tumors recruit more immunosuppressive cells to TME and promote polarization toward pro-tumor phenotype. (f) Oncogene mutation and abnormal activation contribute to inhibition of antitumor immunity, resulting in primary resistance to anti-PD1/PDL1 therapy.