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Fig. 4 | Journal for ImmunoTherapy of Cancer

Fig. 4

From: Prospects for combined use of oncolytic viruses and CAR T-cells

Fig. 4

Immunosuppressive influences on CAR-T cell effector function within the tumour microenvironment. A large number of molecular and cellular players have been implicated in the development of an immunosuppressive milieu non-conducive to anti-tumoural T-cell recruitment, trafficking and effector function. Successful implementation of CAR T-cell therapy for solid tumours will necessitate the targeting of many of these players. Key environmental factors include: intra-tumoural hypoxia (exacerbated by VEGF); low pH (in part due to tumour cell lactic acid production); deficiencies of critical or semi-critical amino acids (e.g. tryptophan via IDO1/TDO or arginine via arginase 1 respectively); high levels of ATP and adenosine; increased COX activity and production of PGE2; high levels of immunosuppressive cytokines such as TGFβ and IL-10; upregulation of immune checkpoints on tumour cells and immune cells (particularly PD-L1, LAG-3 and TIM-3); the presence of a relatively impenetrable ECM; and high levels of reactive oxygen and nitrogen species [58]. Many of these factors either directly limit CAR T-cell function or augment the differentiation, recruitment, proliferation and immunosuppressive function of local immune cells within the TME such as Tregs, MDSCs, TAMs and CAFs [14]. DCs are also rendered dysfunctional and whilst CARs can target TAAs or TSAs independent of DC cross-priming, CAR T-cell trafficking and effector function are likely to be negatively impacted by DC dysfunction and loss of CXCL-9/10 chemokine signalling particularly [75]. In addition, high levels of VEGF and hypoxia may limit CAR T-cell entry by causing local disruption of the vascular endothelium and the downregulation of cell surface adhesion molecules [223] to aid CAR T-cell rolling and intra-tumoural migration

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