Immunotherapeutic Potential of TGF-β Inhibition and Oncolytic Viruses

Immune checkpoint blockade is not effective in immune-excluded and -desert tumors due to an immunosuppressive tumor microenvironment and the absence of activated T cells. TGF-β is a pleiotropic cytokine that contributes to immune exclusion and evasion in various cancer types. The therapeutic efficacy of oncolytic viruses is built on the recruitment of T cells and the induction of tumor-reactive immunity. Oncolytic virotherapy and inhibition of TGF-β signaling, either alone or in combination, are two emerging approaches to increase the susceptibility of immune-silent tumors to immune checkpoint therapy. In cancer immunotherapy, a patient’s own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-β (TGF-β)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-β signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade. In cancer immunotherapy, a patient’s own immune system is harnessed against cancer. Immune checkpoint inhibitors release the brakes on tumor-reactive T cells and, therefore, are particularly effective in treating certain immune-infiltrated solid tumors. By contrast, solid tumors with immune-silent profiles show limited efficacy of checkpoint blockers due to several barriers. Recent discoveries highlight transforming growth factor-β (TGF-β)-induced immune exclusion and a lack of immunogenicity as examples of these barriers. In this review, we summarize preclinical and clinical evidence that illustrates how the inhibition of TGF-β signaling and the use of oncolytic viruses (OVs) can increase the efficacy of immunotherapy, and discuss the promise and challenges of combining these approaches with immune checkpoint blockade. fusion proteins comprising two different single-chain variable fragments of monoclonal antibodies for simultaneous tumor cell binding and T cell activation. cell type within the tumor stroma that can promote tumor progression by ECM remodeling and secretion of cytokines. immune checkpoint receptor that downregulates T cell responses. CD8+ effector T cells; important for the elimination of intracellular pathogens and malignant cells. endogenous molecules released from damaged cells, initiating a noninfectious inflammatory response. antigen-presenting cells specialized in priming of naïve T cells. process by which epithelial cells dedifferentiate towards migratory and invasive mesenchymal stem cells. network of extracellular macromolecules, such as collagen. tumor phenotype without evident immune response. tumor phenotype where tumor-reactive T cells are unable to infiltrate tumor beds due to a physical or immunosuppressive barrier. tumor phenotype where inflammation is present and T lymphocytes have infiltrated the tumor. ability to evoke an adaptive immune response. treatment focused on mobilizing the host immune system to combat disease. cells of the myeloid lineage with strong immunosuppressive properties that have been associated with tumor progression. antigens that result from tumor-specific mutations and are absent from the normal genome. viruses that preferentially replicate in and kill cancer cells. experimental model where a transplanted tumor is placed in the organ of the original tumor. molecules derived from bacteria or viruses that evoke an inflammatory reaction. process in which naïve T cells encounter an antigen in the context of, for example, an activated DC, and start clonal expansion. immune checkpoint receptor expressed on the cell surface of T cells, which negatively regulates T cell responses. FoxP3-expressing CD4+ T lymphocytes that functionally suppress effector T cells. low-molecular-weight compounds that block the action of one or more enzymes called protein kinases. genetically modified oncolytic HSV-1, designed to produce GM-CSF; FDA approved for the treatment of melanoma. functionally inactivated state of T cells after antigen encounter. progressive loss of effector function in T cells due to prolonged antigen stimulation. multifunctional secreted protein with three isoforms, involved in regulating and mediating many cellular processes. proteins or substances produced in tumor cells that can be recognized by the adaptive immune system. molecules, cells, and vessels that surround and interact with the tumor cells. macrophages found in tumors that exhibit immunosuppressive properties. white blood cells that have migrated into the tumor.