TY - JOUR
T1 - Pleiotrophin drives a prometastatic immune niche in breast cancer
AU - Ganguly, Debolina
AU - Schmidt, Marcel O.
AU - Coleman, Morgan
AU - Ngo, Tuong Vi Cindy
AU - Sorrelle, Noah
AU - Dominguez, Adrian T.A.
AU - Murimwa, Gilbert Z.
AU - Toombs, Jason E.
AU - Lewis, Cheryl
AU - Fang, Yisheng V.
AU - Valdes-Mora, Fatima
AU - Gallego-Ortega, David
AU - Wellstein, Anton
AU - Brekken, Rolf A.
N1 - Publisher Copyright:
© 2023 Ganguly et al.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
AB - Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-κB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment, and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor-associated neutrophils and reverts local immune suppression, resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade and chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a prometastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
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U2 - 10.1084/jem.20220610
DO - 10.1084/jem.20220610
M3 - Article
C2 - 36828390
AN - SCOPUS:85176370999
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 5
M1 - e20220610
ER -