IDO Silencing for Cancer Therapy

Indoleamine 2,3-dioxygenase (IDO) is a natural immunoregulatory mechanism that contributes to immune suppression and tolerance in a variety of settings. It directly inhibits the proliferation and differentiation of effector T cells and significantly enhances the inhibitory activity of regulatory T cells. Creative Biolabs provides IDO vaccine development for cancer therapy by helping the immune system to respond effectively to tumor antigens. Treatment of IDO-inhibitor drugs enhances anti-tumor immune responses and can be synergistic with other forms of immunotherapy and anti-tumor vaccines.

Biochemical Mechanism of IDO

As an evolutionarily ancient enzyme, indoleamine 2,3-dioxygenase (IDO) can degrade the amino acid tryptophan. The normal role of IDO is to promote certain forms of acquired peripheral tolerance and to control excessive inflammation in the immune system. In tissues, local expression of IDO controls innate immunity and excessive inflammation caused by chronic infection. IDO can also induce antigen-specific tolerance in T cells. This natural effect may become pathologic when abnormal expression of IDO is driven by tumors.

Fig.1 IDO-mediated tryptophan degradation by DCs results in multiple effects, including inhibition of T-cell proliferation, increased T-cell apoptosis, and de novo formation of Tregs. (Antonio, C. 2009)

IDO and Cancer

It is shown that resting T cells initially become aware of tumor antigens primarily through cross-presentation of host antigen-presenting cells. The tumor actively alters the local microenvironment and draining lymph nodes, making antigen presentation that occurs in this environment become viable and tolerant. IDO is an important cellular factor that promotes immunosuppression and is, therefore, part of a key mechanism in cancer. For this reason, IDO is a very attractive target in the design of new anti-cancer drugs. Several IDO inhibitors have been studied in preclinical and clinical studies. Analysis of lymph nodes draining sites of established tumors often show abnormal over-expression of IDO. IDO has been confirmed by immunohistochemistry in a variety of human cancers, including pancreatic cancer, colorectal cancer, malignant melanoma, ovarian cancer, prostate cancer, acute myelogenous leukemia and endometrial cancer.

IDO Vaccine

IDO vaccines are different from IDO blockers in several ways. When the IDO vaccine induces IDO-specific T cells, pro-inflammatory T cells are attracted to the tumor microenvironment. Importantly, IDO vaccines can also function in tumors where the cancer cells themselves do not express targets and in tumors with low HLA expression compared to traditional tumor antigen-specific vaccines. IDO specific T cells can support anti-cancer immunity in different ways: 1) Modulating the tumor microenvironment by releasing pro-inflammatory cytokines that attack and help other immune cells at the tumor site; 2) Direct killing of immune-suppressive target cells including tumor cells.

In addition to inhibiting the immune-regulatory effects of IDO, IDO-specific T cells also inhibit other immune suppression pathways mediated by IDO⁺ target cells. Therefore, IDO-specific T cells do not directly target the enzyme IDO, but target cells that express IDO. Thus, the IDO vaccine reduces not only IDO-mediated immune suppression but also general immune-suppressive effects mediated by IDO⁺ cells. Hence, combinatorial therapy using IDO vaccine and checkpoint blockade should be effective in a broader population of cancer patients.

Chemo-Immunotherapy with IDO-Inhibitor Drugs

Standard chemotherapy drugs can be administered in combination with anti-tumor immunotherapy in some cases to produce synergistic effects. Preclinical studies of mouse tumor models have shown that the IDO inhibitor 1-methyl-tryptophan exhibits synergy when combined with a variety of chemotherapeutic drugs. IDO plays a fundamental and widely-applicable biologic role in helping suppress the host anti-tumor immune response following chemotherapy.

IDO is located at the intersection of three key immunosuppressive pathways: inhibition of effector T cells, activation of Tregs, and suppression of inflammation. Pharmacologic inhibition of IDO may be synergistic with existing active immunotherapy, especially if administered in the window of opportunity following conventional chemotherapy. Creative Biolabs is a leader in the field of vaccine development and has focused on the cancer vaccines for years. We have experienced experts and advanced platforms that are able to provide excellent services. If you are interested in our services, please contact us for more details.

Reference

1. Antonio, C. (2009). “The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology.” Blood.

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