Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab results in durable responses in metastatic melanoma, though therapeutic benefit has been limited to a fraction of patients. This calls for identification of resistance mechanisms and development of combinatorial strategies. Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. In IDO knockout mice treated with anti-CTLA-4 antibody, we demonstrate a striking delay in B16 melanoma tumor growth and increased overall survival when compared with wild-type mice. This was also observed with antibodies targeting PD-1-PD-L1 and GITR. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.
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PMID:Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. 2375 27

Interleukin 4 (IL4)-induced gene 1 (IL4I1) is an oxidase that degrades l-phenylalanine into phenylpyruvate, hydrogen peroxide, and ammonia. In contrast to other amino acid catabolic enzymes (i.e., indoleamine 2,3-dioxygenase and inducible nitric oxide synthase), IL4I1 is expressed not only in an intracellular form but also an active secreted form. Although about 20 yr ago IL4I1 was identified in murine B cells in response to IL4, we only recently established its key role in controlling B-cell receptor-mediated signaling during murine B-cell ontogeny and responses in physiological settings. Genetic IL4I1 invalidation increases the number of tumor-associated B cells and delays development of spontaneous metastatic melanoma in mice that are transgenic for the RET oncogene, without impairing tumor-specific antibody response. Although no consensus exists on phenotype and functions of melanoma-associated B cells, our results in RET mice argue for a protective role, with IL4I1 dampening this benefit. However, regulation of IL4I1 expression in innate-like and conventional B-cell subsets and its impact on B-cell properties are incompletely known, in particular, in cancer settings. This review aims to summarize our present knowledge of B cells in human and murine melanoma and address emerging questions about the impact of IL4I1 on B-cell functions in physiological and cancer settings. We note that during melanoma progression, IL4I1 may selectively be expressed by regulatory B cells and/or indirectly promote B-cell-mediated immunosuppression.
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PMID:Interleukin 4-Induced Gene 1 as an Emerging Regulator of B-Cell Biology and its Role in Cutaneous Melanoma. 3167 93