TY - JOUR
T1 - Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors
AU - Kumar, Vinit
AU - Donthireddy, Laxminarasimha
AU - Marvel, Douglas
AU - Condamine, Thomas
AU - Wang, Fang
AU - Lavilla-Alonso, Sergio
AU - Hashimoto, Ayumi
AU - Vonteddu, Prashanthi
AU - Behera, Reeti
AU - Goins, Marlee A.
AU - Mulligan, Charles
AU - Nam, Brian
AU - Hockstein, Neil
AU - Denstman, Fred
AU - Shakamuri, Shanti
AU - Speicher, David W.
AU - Weeraratna, Ashani T.
AU - Chao, Timothy
AU - Vonderheide, Robert H.
AU - Languino, Lucia R.
AU - Ordentlich, Peter
AU - Liu, Qin
AU - Xu, Xiaowei
AU - Lo, Albert
AU - Puré, Ellen
AU - Zhang, Chunsheng
AU - Loboda, Andrey
AU - Sepulveda, Manuel A.
AU - Snyder, Linda A.
AU - Gabrilovich, Dmitry I.
N1 - Funding Information:
This work was supported by Janssen R&D and Syndax Pharmaceuticals as well as NIH grants RO1 CA084488, P01 CA140043 , P50 CA168536 , and P01 CA114046 . P.O. is an employee of Syndax Pharmaceuticals; M.A.S. and L.A.S. are employees of Janssen R&D; C.Z. and A.L. are employees of Merck, Kenilworth, NJ, USA.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/11/13
Y1 - 2017/11/13
N2 - 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. Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.
AB - 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. Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer-associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.
KW - CSF1R
KW - M-CSF
KW - PMN-MDSC
KW - fibroblasts
KW - granulocytes
KW - macrophages
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U2 - 10.1016/j.ccell.2017.10.005
DO - 10.1016/j.ccell.2017.10.005
M3 - Article
C2 - 29136508
AN - SCOPUS:85033725863
SN - 1535-6108
VL - 32
SP - 654-668.e5
JO - Cancer cell
JF - Cancer cell
IS - 5
ER -