CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8+ T cells
Debbie C Strachan,Brian Ruffell,Yoko Oei,Mina J. Bissell,Lisa M. Coussens,Nancy Pryer,Dylan Daniel +6 more
Reads0
Chats0
TLDR
The results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF 1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.Abstract:
Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma. The blockade of CSF1R signaling has been shown to greatly decrease the number of macrophages in a tissue-specific manner. However, additional mechanistic insights are needed in order to understand how macrophages are depleted and the global effects of CSF1R inhibition on other tumor-infiltrating immune cells. Using BLZ945, a highly selective small molecule inhibitor of CSF1R, we show that CSF1R inhibition attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. Specifically, we find that BLZ945 decreased the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. Furthermore, we show that BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Our results demonstrate that TAMs undergo a constant turnover in a CSF1R-dependent manner, and suggest that continuous inhibition of the CSF1R pathway may be essential to maintain efficacious macrophage depletion as an anticancer therapy.read more
Citations
More filters
Journal ArticleDOI
Tumor-associated macrophages: from mechanisms to therapy.
TL;DR: Therapeutic success in targeting these protumoral roles in preclinical models and in early clinical trials suggests that macrophages are attractive targets as part of combination therapy in cancer treatment.
Journal ArticleDOI
T cell exclusion, immune privilege, and the tumor microenvironment
TL;DR: Evidence is reviewed that stromal cells of the tumor microenvironment mediate this restriction by excluding T cells from the vicinity of cancer cells, and overcoming this T cell checkpoint may enable optimal immunotherapy.
Journal ArticleDOI
Macrophages as regulators of tumour immunity and immunotherapy
David G. DeNardo,Brian Ruffell +1 more
TL;DR: How macrophage shape local immune responses in the tumour microenvironment to both suppress and promote immunity to tumours is described and the potential of targeting tumour-associated macrophages to enhance antitumour immune responses is discussed.
Journal ArticleDOI
Macrophages and Therapeutic Resistance in Cancer
Brian Ruffell,Lisa M. Coussens +1 more
TL;DR: This review discusses the molecular/cellular pathways identified so far whereby macrophages mediate therapeutic responses and therapeutics impacting macrophage presence and/or bioactivity have shown promise in preclinical models and are now being evaluated in the clinic.
Journal ArticleDOI
Targeting Tumor-Associated Macrophages with Anti-CSF-1R Antibody Reveals a Strategy for Cancer Therapy
Carola Ries,Michael A. Cannarile,Sabine Hoves,Jörg Benz,Katharina Wartha,Valeria Runza,Flora Rey-Giraud,Leon P. Pradel,Friedrich Feuerhake,Irina Klaman,Tobin Jones,Ute Jucknischke,Stefan Scheiblich,Klaus Kaluza,Ingo H. Gorr,Antje Walz,Keelara Abiraj,Philippe A. Cassier,Antonio Sica,Carlos Gomez-Roca,Karin E. de Visser,Antoine Italiano,Christophe Le Tourneau,Jean-Pierre Delord,Hyam I. Levitsky,Jean-Yves Blay,Dominik Rüttinger +26 more
TL;DR: Administration of RG7155 to patients led to striking reductions of CSF-1R(+)CD163(+) macrophages in tumor tissues, which translated into clinical objective responses in diffuse-type giant cell tumor (Dt-GCT) patients.
References
More filters
Journal ArticleDOI
Exploring the full spectrum of macrophage activation.
TL;DR: This Review suggests a new grouping of macrophages based on three different homeostatic activities — host defence, wound healing and immune regulation, and proposes that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation.
Journal ArticleDOI
Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes
Alberto Mantovani,Silvano Sozzani,Silvano Sozzani,Massimo Locati,Paola Allavena,Antonio Sica +5 more
TL;DR: These functionally polarized cells, and similarly oriented or immature dendritic cells present in tumors, have a key role in subversion of adaptive immunity and in inflammatory circuits that promote tumor growth and progression.
Journal ArticleDOI
Macrophage Diversity Enhances Tumor Progression and Metastasis
Bin-Zhi Qian,Jeffrey W. Pollard +1 more
TL;DR: There is persuasive clinical and experimental evidence that macrophages promote cancer initiation and malignant progression, and specialized subpopulations of macrophage may represent important new therapeutic targets.
Journal ArticleDOI
Alternative Activation of Macrophages: An Immunologic Functional Perspective
TL;DR: The cellular sources of these cytokines, receptor signaling pathways, and induced markers and gene signatures are reviewed and the concept of macrophage activation in the context of the immune response is revisit.
Journal ArticleDOI
CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis
Bin-Zhi Qian,Jiufeng Li,Hui Zhang,Takanori Kitamura,Jinghang Zhang,Liam Campion,Elizabeth Kaiser,Linda A. Snyder,Jeffrey W. Pollard +8 more
TL;DR: The mechanistic link between CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer and the origin of these macrophages is defined by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice.
Related Papers (5)
CSF-1R inhibition alters macrophage polarization and blocks glioma progression
Stephanie M. Pyonteck,Leila Akkari,Alberto J. Schuhmacher,Robert L. Bowman,Lisa Sevenich,Daniela F. Quail,Oakley C. Olson,Marsha L. Quick,Jason T. Huse,Virginia Teijeiro,Manu Setty,Christina S. Leslie,Yoko Oei,Alicia Pedraza,Jianan Zhang,Cameron Brennan,James Sutton,Eric C. Holland,Dylan Daniel,Johanna A. Joyce +19 more
Macrophage Diversity Enhances Tumor Progression and Metastasis
Bin-Zhi Qian,Jeffrey W. Pollard +1 more