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Fig. 1 | Journal for ImmunoTherapy of Cancer

Fig. 1

From: Toward a comprehensive view of cancer immune responsiveness: a synopsis from the SITC workshop

Fig. 1

Germline contributions to CIR. Germline genetic contributions to CIR. Genetic germline variants can influence CIR in different ways, which are tightly interconnected. Variants associated with attitude to smoke or mutation in DNA-repair genes (e.g., DNA mismatch repair genes) can cause the accumulation of somatic alterations which in turn might facilitate the parallel development of neoepitope-mediated immune recognition.. Polymorphisms of genes that modulate critical immunologic pathways such as IFN signaling and differentiation and function of T cells and B cells might influence the development of tolerant vs cytotoxic TME. The same could be said of variants in genes governing antigen presentation such as HLA class I and II, ICD, innate-immunity function in macrophages, natural killer (NK) cells, and granulocytes. Polymorphisms of TLR4, P2RX7, and FPR1 have been associated with differential outcome in breast and colon cancer patients treated with adjuvant chemotherapy, likely through the modulation of ICD-mediated anti-tumor immune response [63, 64]. HLA-E, a non-classical HLA molecule, is recognized by specific NK cell lectin-type receptors with either activating or inhibiting activity in the context of specific and redundant antigenic presentation. HLA-E polymorphisms might have an impact on anti-tumor response independently from the CIR mechanisms recognized so far [65]. Variants in genes encoding for chemokines or chemokine receptors might also differentially modulate intra-tumoral recruitment of immune cells. Variations in protein-coding regions of genes affecting structure or expression of molecules targeted by IO agents might influence their efficacy. Polymorphisms of crystallizable fragment (Fc)-γ receptor genes have been associated, although inconsistently, with distinct outcomes in patients treated with Rituximab and Trastuzumab [66]. Such variations might potentially influence the efficacy ICIs via antibody-dependent cytotoxicity (ADCC) lysis of target or tumor cells [67]

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