TY - JOUR
T1 - Chemerin suppresses breast cancer growth by recruiting immune effector cells into the tumor microenvironment
AU - Pachynski, Russell K.
AU - Wang, Ping
AU - Salazar, Nicole
AU - Zheng, Yayue
AU - Nease, Leona
AU - Rosalez, Jesse
AU - Leong, Weng In
AU - Virdi, Gurpal
AU - Rennier, Keith
AU - Shin, Woo Jae
AU - Nguyen, Viet
AU - Butcher, Eugene C.
AU - Zabel, Brian A.
N1 - Funding Information:
This work is supported by NIH/NIAID R01 CA169354 (EB, RP), American Cancer Society MSRG 125078-MRSG-13-244-01-LIB, California Breast Cancer Research Program, ASCO YIA, and the Kimmel Foundation (RP). This work was also supported by the NIH (R01AI079320 to BZ; R01CA169354 and R01GM037734 to EB), and the Emerson Collective Cancer Research Fund (BZ and EB). This work was supported in part by Merit Review Award Number I01 BX004115 from the United States (U.S.) Department of Veterans Affairs Biomedical Laboratory R&D (BLRD) Service to BZ. NS was supported by a diversity supplement from the NIH (3R01CA169354-03S1), and JR was supported by an SJSU NIH-MARC fellowship from the NIGMS Grant #4T34GM008253-30.
Funding Information:
We are grateful to Dr. Marshall Poger for his help with pathologic review and analyses of human tissues. We would like to thank Kayla Corman and Christina Mizerny for administrative support. We kindly thank Tom Walsh and the St. Louis Breast Tissue Registry for production of human breast tissue microarrays. We thank the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital in St. Louis, MO. and the Institute of Clinical and Translational Sciences (ICTS) at Washington University in St. Louis, for the use of the Tissue Procurement Core, which provided human breast tissue RNA. The Siteman Cancer Center is supported in part by an NCI Cancer Center Support Grant #P30 CA091842 and the ICTS is funded by the National Institutes of Health’s NCATS Clinical and Translational Science Award (CTSA) program grant #UL1 TR002345.
Publisher Copyright:
Copyright © 2019 Pachynski, Wang, Salazar, Zheng, Nease, Rosalez, Leong, Virdi, Rennier, Shin, Nguyen, Butcher and Zabel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
PY - 2019
Y1 - 2019
N2 - Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.
AB - Infiltration of immune cells into the tumor microenvironment (TME) can regulate growth and survival of neoplastic cells, impacting tumorigenesis and tumor progression. Correlations between the number of effector immune cells present in a tumor and clinical outcomes in many human tumors, including breast, have been widely described. Current immunotherapies utilizing checkpoint inhibitors or co-stimulatory molecule agonists aim to activate effector immune cells. However, tumors often lack adequate effector cell numbers within the TME, resulting in suboptimal responses to these agents. Chemerin (RARRES2) is a leukocyte chemoattractant widely expressed in many tissues and is known to recruit innate leukocytes. CMKLR1 is a chemotactic cellular receptor for chemerin and is expressed on subsets of dendritic cells, NK cells, and macrophages. We have previously shown that chemerin acts as a tumor suppressive cytokine in mouse melanoma models by recruiting innate immune defenses into the TME. Chemerin/RARRES2 is down-regulated in many tumors, including breast, compared to normal tissue counterparts. Here, using a syngeneic orthotopic EMT6 breast carcinoma model, we show that forced overexpression of chemerin by tumor cells results in significant recruitment of NK cells and T cells within the TME. While chemerin secretion by EMT6 cells did not alter their phenotypic behavior in vitro, it did significantly suppress tumor growth in vivo. To define the cellular effectors required for this anti-tumor phenotype, we depleted NK cells or CD8+ T cells and found that either cell type is required for chemerin-dependent suppression of EMT6 tumor growth. Finally, we show significantly reduced levels of RARRES2 mRNA in human breast cancer samples compared to matched normal tissues. Thus, for the first time we have shown that increasing chemerin expression within the breast carcinoma TME can suppress growth by recruitment of NK and T cells, thereby supporting this approach as a promising immunotherapeutic strategy.
KW - Breast cancer
KW - Chemerin
KW - Immunotherapy
KW - Leukocyte trafficking
KW - NK cells
KW - RARRES2
KW - T cells
UR - http://www.scopus.com/inward/record.url?scp=85067309785&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2019.00983
DO - 10.3389/fimmu.2019.00983
M3 - Article
C2 - 31139180
AN - SCOPUS:85067309785
SN - 1664-3224
VL - 10
JO - Frontiers in Immunology
JF - Frontiers in Immunology
IS - MAY
M1 - 983
ER -