Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
(1) Kumar V (2) Donthireddy L (3) Marvel D (4) Condamine T (5) Wang F (6) Lavilla-Alonso S (7) Hashimoto A (8) Vonteddu P (9) Behera R (10) Goins MA (11) Mulligan C (12) Nam B (13) Hockstein N (14) Denstman F (15) Shakamuri S (16) Speicher DW (17) Weeraratna AT (18) Chao T (19) Vonderheide RH (20) Languino LR (21) Ordentlich P (22) Liu Q (23) Xu X (24) Lo A (25) Pure E (26) Zhang C (27) Loboda A (28) Sepulveda MA (29) Snyder LA (30) Gabrilovich DI
To understand why depletion of tumor-associated macrophages (TAMs) by CSF1R inhibition has little to no antitumor effect, Kumar et al. systematically explored the mechanism and found that while TAMs do get depleted, CSF1R inhibition also causes carcinoma-associated fibroblasts to secrete cytokines that recruit pro-tumor PMN-MDSCs to the tumor site. Using CSF1R inhibitors in combination with a CXCR2 inhibitor to prevent PMN-MDSC recruitment delayed tumor growth and enhanced the therapeutic effect of PD-1 inhibition in mice.
(1) Kumar V (2) Donthireddy L (3) Marvel D (4) Condamine T (5) Wang F (6) Lavilla-Alonso S (7) Hashimoto A (8) Vonteddu P (9) Behera R (10) Goins MA (11) Mulligan C (12) Nam B (13) Hockstein N (14) Denstman F (15) Shakamuri S (16) Speicher DW (17) Weeraratna AT (18) Chao T (19) Vonderheide RH (20) Languino LR (21) Ordentlich P (22) Liu Q (23) Xu X (24) Lo A (25) Pure E (26) Zhang C (27) Loboda A (28) Sepulveda MA (29) Snyder LA (30) Gabrilovich DI
To understand why depletion of tumor-associated macrophages (TAMs) by CSF1R inhibition has little to no antitumor effect, Kumar et al. systematically explored the mechanism and found that while TAMs do get depleted, CSF1R inhibition also causes carcinoma-associated fibroblasts to secrete cytokines that recruit pro-tumor PMN-MDSCs to the tumor site. Using CSF1R inhibitors in combination with a CXCR2 inhibitor to prevent PMN-MDSC recruitment delayed tumor growth and enhanced the therapeutic effect of PD-1 inhibition in mice.
Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects.
Author Info:
(1) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (2) Immunology, Microenvironment and Metastasis Program, The Wistar Inst
itute, Philadelphia, PA 19104, USA. (3) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (4) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (5) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (6) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (7) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (8) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (9) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (10) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (11) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (12) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (13) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (14) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (15) Helen F. Graham Cancer Center at Christiana Care Health System, Wilmington, DE, USA. (16) Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (17) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (18) University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. (19) University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. (20) Sidney Kimmel Cancer Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA. (21) Syndax Pharmaceuticals, Inc., Waltham, MA 02451, USA. (22) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. (23) University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. (24) University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA. (25) University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA. (26) Department of Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USA. (27) Department of Genetics and Pharmacogenomics, MRL, Merck & Co., Inc., Boston, MA 02115, USA. (28) Janssen R&D, Spring House, PA 19477, USA. (29) Janssen R&D, Spring House, PA 19477, USA. (30) Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: dgabrilovich@wistar.org.
Citation: Cancer Cell 2017 Nov 13 32:654-668.e5 Epub
