Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy

Terry R. Medler; Dhaarini Murugan; Wesley Horton; Sushil Kumar; Tiziana Cotechini; Alexandra M. Forsyth; Patrick Leyshock; Justin J. Leitenberger; Molly Kulesz-Martin; Adam A. Margolin; Zena Werb; Lisa M. Coussens

doi:10.1016/j.ccell.2018.09.003

Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy

Terry R. Medler
, Dhaarini Murugan
, Wesley Horton
, Sushil Kumar
, Tiziana Cotechini
, Alexandra M. Forsyth
, Patrick Leyshock
, Justin J. Leitenberger
, Molly Kulesz-Martin
, Adam A. Margolin
, Zena Werb
, Lisa M. Coussens

Research output: Contribution to journal › Article › peer-review

163 Scopus citations

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.

Original language	English
Pages (from-to)	561-578.e6
Journal	Cancer Cell
Volume	34
Issue number	4
DOIs	https://doi.org/10.1016/j.ccell.2018.09.003
State	Published - 8 Oct 2018
Externally published	Yes

Keywords

CD8 T cell
complement C5a
immunotherapy
inflammation
macrophage
squamous cell carcinoma
urokinase

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10.1016/j.ccell.2018.09.003

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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 Margolin, \{Adam A.\} and Zena Werb and Coussens, \{Lisa M.\}",

note = "Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.ccell.2018.09.003",

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T1 - Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy

AU - Medler, Terry R.

AU - Murugan, Dhaarini

AU - Horton, Wesley

AU - Kumar, Sushil

AU - Cotechini, Tiziana

AU - Forsyth, Alexandra M.

AU - Leyshock, Patrick

AU - Leitenberger, Justin J.

AU - Kulesz-Martin, Molly

AU - Margolin, Adam A.

AU - Werb, Zena

AU - Coussens, Lisa M.

PY - 2018/10/8

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N2 - 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.

AB - 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.

KW - CD8 T cell

KW - complement C5a

KW - immunotherapy

KW - inflammation

KW - macrophage

KW - squamous cell carcinoma

KW - urokinase

UR - https://www.scopus.com/pages/publications/85053842719

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DO - 10.1016/j.ccell.2018.09.003

M3 - Article

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AN - SCOPUS:85053842719

SN - 1535-6108

VL - 34

SP - 561-578.e6

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Complement C5a Fosters Squamous Carcinogenesis and Limits T Cell Response to Chemotherapy

Abstract

Keywords

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