@article{51565d94be75455a89d6924c4b94fa09,
title = "Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy",
abstract = "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. Medler et al. find that C3-independent C5a release mediated by uPA+ macrophages fosters an immunosuppressive microenvironment during squamous carcinogenesis by activating C5aR1+ mast cells and macrophages. C5aR1 inhibition improves paclitaxel efficacy by reprogramming macrophages to recruit cytotoxic CD8+ T cells.",
keywords = "CD8 T cell, complement C5a, immunotherapy, inflammation, macrophage, squamous cell carcinoma, urokinase",
author = "Medler, {Terry R.} and Dhaarini Murugan and Wesley Horton and Sushil Kumar and Tiziana Cotechini and Forsyth, {Alexandra M.} and Patrick Leyshock and Leitenberger, {Justin J.} and Molly Kulesz-Martin and Adam Margolin and Zena Werb and Coussens, {Lisa M.}",
note = "Funding Information: The authors thank the Knight Cancer Institute ( P30 CA069533 ) Flow Cytometry, Advanced Light Microscopy, Bioinformatics, and OHSU Massively Parallel Sequencing shared resources. Human tissue specimens provided by the OHSU Department of Dermatology Molecular Profiling Tissue Resource Repository (IRB#10071). We are grateful to members of the Coussens Lab for critical discussions; to Ole Behrendtsen, Lia Kim, Miriam Marx, Shiv Shah, and Meghan Lavoie for technical assistance; to Justin Tibbitts and Teresa Beechwood for research regulatory oversight and animal husbandry; and to Drs. Leif Lund and Keld Dano for providing uPA −/− mice. The authors acknowledge support from the American Cancer Society – Friends of Robert Kinas Postdoctoral Fellowship ( PF-14-221-01-MPC ), NIH/ NCI Postdoctoral Training Grant ( CA106195 ), the Cathy and Jim Rudd Career Development Award for Cancer Research, the Medical Research Foundation, and Drs. Gough and Crittenden for salary support during manuscript revision to T.R.M.; NIH/NCI ( CA192405 ) to M.K.-M.; NIH/NCI ( CA057621 ) to Z.W.; and the NIH/NCI ( CA130980 , CA155331 , CA163123 ), a DOD BCRP Era of Hope Scholar Expansion Award (W81XWH-08-PRMRP-IIRA), the Susan G. Komen Foundation ( KG110560 ), the Breast Cancer Research Foundation , the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant ( SU2C-AACR-DT14-14 ) to L.M.C. Funding Information: The authors thank the Knight Cancer Institute (P30 CA069533) Flow Cytometry, Advanced Light Microscopy, Bioinformatics, and OHSU Massively Parallel Sequencing shared resources. Human tissue specimens provided by the OHSU Department of Dermatology Molecular Profiling Tissue Resource Repository (IRB#10071). We are grateful to members of the Coussens Lab for critical discussions; to Ole Behrendtsen, Lia Kim, Miriam Marx, Shiv Shah, and Meghan Lavoie for technical assistance; to Justin Tibbitts and Teresa Beechwood for research regulatory oversight and animal husbandry; and to Drs. Leif Lund and Keld Dano for providing uPA−/− mice. The authors acknowledge support from the American Cancer Society – Friends of Robert Kinas Postdoctoral Fellowship (PF-14-221-01-MPC), NIH/NCI Postdoctoral Training Grant (CA106195), the Cathy and Jim Rudd Career Development Award for Cancer Research, the Medical Research Foundation, and Drs. Gough and Crittenden for salary support during manuscript revision to T.R.M.; NIH/NCI (CA192405) to M.K.-M.; NIH/NCI (CA057621) to Z.W.; and the NIH/NCI (CA130980, CA155331, CA163123), a DOD BCRP Era of Hope Scholar Expansion Award (W81XWH-08-PRMRP-IIRA), the Susan G. Komen Foundation (KG110560), the Breast Cancer Research Foundation, the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer – Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT14-14) to L.M.C. Funding Information: The authors thank the Knight Cancer Institute (P30 CA069533) Flow Cytometry, Advanced Light Microscopy, Bioinformatics, and OHSU Massively Parallel Sequencing shared resources. Human tissue specimens provided by the OHSU Department of Dermatology Molecular Profiling Tissue Resource Repository (IRB#10071). We are grateful to members of the Coussens Lab for critical discussions; to Ole Behrendtsen, Lia Kim, Miriam Marx, Shiv Shah, and Meghan Lavoie for technical assistance; to Justin Tibbitts and Teresa Beechwood for research regulatory oversight and animal husbandry; and to Drs. Leif Lund and Keld Dano for providing uPA?/? mice. The authors acknowledge support from the American Cancer Society ? Friends of Robert Kinas Postdoctoral Fellowship (PF-14-221-01-MPC), NIH/NCI Postdoctoral Training Grant (CA106195), the Cathy and Jim Rudd Career Development Award for Cancer Research, the Medical Research Foundation, and Drs. Gough and Crittenden for salary support during manuscript revision to T.R.M.; NIH/NCI (CA192405) to M.K.-M.; NIH/NCI (CA057621) to Z.W.; and the NIH/NCI (CA130980, CA155331, CA163123), a DOD BCRP Era of Hope Scholar Expansion Award (W81XWH-08-PRMRP-IIRA), the Susan G. Komen Foundation (KG110560), the Breast Cancer Research Foundation, the Brenden-Colson Center for Pancreatic Health, and a Stand Up To Cancer ? Lustgarten Foundation Pancreatic Cancer Convergence Dream Team Translational Research Grant (SU2C-AACR-DT14-14) to L.M.C. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = oct,
day = "8",
doi = "10.1016/j.ccell.2018.09.003",
language = "English (US)",
volume = "34",
pages = "561--578.e6",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}