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Ref Type Journal Article
PMID (30300579)
Authors Medler TR, Murugan D, Horton W, Kumar S, Cotechini T, Forsyth AM, Leyshock P, Leitenberger JJ, Kulesz-Martin M, Margolin AA, Werb Z, Coussens LM
Title Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy.
Journal Vol Issue Date Pages Journal Short Title
Cancer cell 34 4 2018 10 08 561-578.e6 Cancer Cell
URL
Abstract Text Complement is a critical component of humoral immunity implicated in cancer development; however, its biological contributions to tumorigenesis remain poorly understood. Using the K14-HPV16 transgenic mouse model of squamous carcinogenesis, we report that urokinase (uPA)+ macrophages regulate C3-independent release of C5a during premalignant progression, which in turn regulates protumorigenic properties of C5aR1+ mast cells and macrophages, including suppression of CD8+ T cell cytotoxicity. Therapeutic inhibition of C5aR1 via the peptide antagonist PMX-53 improved efficacy of paclitaxel chemotherapy associated with increased presence and cytotoxic properties of CXCR3+ effector memory CD8+ T cells in carcinomas, dependent on both macrophage transcriptional programming and IFNγ. Together, these data identify C5aR1-dependent signaling as an important immunomodulatory program in neoplastic tissue tractable for combinatorial cancer immunotherapy.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PMX-53 PMX-53 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PMX-53 PMX53|PMX 53 PMX-53 is a peptide antagonist that inhibits CD88 (C5AR1), eliciting an antitumor response and potentially resulting in tumor growth inhibition when combined with a chemotherapeutic agent (PMID: 30300579).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References