Targeting Tumor-Related Immunosuppression for Cancer Immunotherapy

Abstract

Tumors produce several factors, such as Prostaglandins (PGs), Interleukin (IL)-10, Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor (TGF)-beta, which may directly or indirectly inhibit the immune response and may hamper immunotherapy. Furthermore, cells of innate or adaptive immunity, recruited by tumor-derived factors, may contribute in immunosuppression. Regulatory T (Treg) cells such as the "naturally occurring" CD4(+)/CD25(+) Treg and the IL-10-induced Tr1 cells are major players in this arena. Paradoxically Treg cells are stimulated by IL-2, which is used in tumor immunotherapy. Treg cells suppress T cell responses through soluble factors or by contact-dependent mechanisms, such as the Cytotoxic T Lymphocyte Antigen (CTLA)-4-mediated induction of Indoleamine 2,3-Dioxygenase (IDO) in dendritic cells (DC). IDO inhibits T cell responses by depleting Tryptophan and producing Kynurenine, which is toxic to lymphocytes. Macrophages, granulocytes or myeloid suppressor cells (MSC) suppress immunity by other enzymatic mechanisms, involving Arginase and Nitric Oxide Synthase (NOS). Subversion of tumor immunosuppression is required for successful immunotherapy. Attempts to block or eliminate Treg cells have been made by the use of chemotherapy, anti-CD25 or anti-CTLA-4 antibodies, IL-2-toxin chimeric proteins or Glucocorticoid-induced TNF-like Receptor (GITR) and CD134/OX-40 ligands. Tumor cells genetically modified to secrete IL-21 (an immune-stimulatory "IL-2-like" cytokine, which is not involved in immune regulation) cured experimental metastases in combination with anti-CD25 monoclonal antibodies (mAbs). Also strategies aimed at blocking enzyme-based immune-suppressive mechanisms are suitable, as suggested by experimental evidences in mouse tumor models.

An adenoviral vector encoding dominant negative Cbl lowers the threshold for T cell activation in post-thymic T cells

“…TCR ligation without costimulation can induce T cell anergy (2) or T cell apoptosis (3). In several in vivo pathologic settings, such as chronic infections or with a progressively growing tumor, the development of T cell dysfunction has been observed (4). Several lines of investigation have suggested that this dysfunction is mediated through immune-intrinsic negative regulatory pathways (5).…”

Enhancement of DNA cancer vaccine efficacy by combination with anti-angiogenesis in regression of established subcutaneous B16 melanoma

“…However therapeutic immunization with the pDNA vaccine could not eradicate established tumor completely. One possibility is that the growing B16F10 tumor secretes immunosuppressive cytokines such as VEGF, IL-10 and TGF-ß which prevent the activated CTLs from entering into the tumor (23,24). Here we find that the efficacy of vaccination can be substantially enhanced by blocking angiogenesis in tumor.…”

Cross-Sectional Study of Gene Expression Analysis Identifies Critical Biological Pathways and Key Genes Implicated in Non-Small Cell Lung Cancer

“…Once the immune system of the host was dysfunctional, tumors escaped the immune surveillance to transform cancers (23). Furthermore, tumor cells released some immunosuppressive cytokines, such as prostaglandins, vascular endothelial growth factor and transforming growth factor-beta to directly or indirectly inhibit the immune response (24). In the GSEA results, the researchers surprisingly found that 12 pathways related to the immune system were significantly down-regulated, which indicated that the immune system was strongly altered/inhibited in NSCLC (25).…”