Figure 1.

Attributes of OVs to overcome immunosuppression by the tumor microenvironment. (A) The immunosuppressive tumor microenvironment. (1) T-cells have poor accessibility to dense, bulky tumors. (2) Presence of immunosuppressive cells such as myeloid derived suppressor cells (MDSCs) and M2 macrophages. (3) Downregulated MHC-I expression resulting in poor antigen presentation/recognition. (4) Tumor cells secrete chemokines attract immunosuppressive cells such as regulatory T-cells (Tregs). (5) Tumor cells can also secrete inhibitory cytokines (e.g., TGF-β, IL-(10) that inhibit cytotoxic T-cell function. (6) Cancer cells often lack tumor specific antigens that can be recognized by endogenous T-cells. (7) Expression of immune checkpoint molecules (e.g., PD-L1) that cause exhaustion upon engagement of cognate receptors on T-cells (e.g., PD-1). (B) Mechanisms by which oncolytic viruses can help T-cells to overcome the immunosuppressive environment. (1) Direct oncolysis of tumor cells and increased tumor accessibility by creating space within the tumor mass. (2) Release of DAMPs, PAMPs, and TAAs upon tumor cell lysis that can recruit APCs, and TAAs can be processed and presented to T-cells at lymph node. (3) OV infection can induce expression of MHC-I and β2M. (4) OVs can be engineered to express chemokines to increase infiltration of both endogenous T-cell and CAR T-cell. (5) Express inflammatory cytokines to increase T-cell proliferation at the tumor site. (6) Produce BiTE (Engager) molecules to redirect T-cells to tumor specific antigens. (7) Express Checkpoint inhibitors for attenuating T-cell exhaustion.