MiR130a and miR145 reprogram immature myeloid cells and inhibit tumor metastasis via improvement of anti-tumor immunity

Authors

• H Ishii
• SK Suman
• BR Achyut
• MC Hollander
• A Lal
• L Yang

Abstract

Immature myeloid cells, identified as Gr1+CD11b+ cells, are expanded in tumor bearing host, and promote distant organ metastasis in tumor bearing host through production of immunosuppressive cytokines and chemokines. Previous studies showed that myeloid specific transforming growth factor beta (TGF¿) signaling is essential for tumor metastasis. Using Lys-Cre mediated myeloid specific Tgfbr2 knockout mice, TGF¿ type II receptor (TbRII) in myeloid cells inhibit tumor metastasis. However, it remains unknown how T¿RII are regulated in myeloid cells during tumor progression. We initially determined that miRs 130 and 145 can directly target Tgfbr2 mRNA by mouse miRNA expression assay, and were down-regulated in Gr1+CD11b+ myeloid cells from 4T1 or Eo771 mammary tumor model. To examine whether miRs130a and 145 inhibit lung metastasis via down-regulation of T¿RII in immature myeloid cells, we used 2 different mouse models with myeloid specific miR130a or miR145 overexpression: 1) 4T1 tumor model transplanted with CD11b driven-miR130a or miR145 engineered bone marrow haematopoietic stem /progenitor cells and 2) Lewis lung carcinoma model with doxycycline-inducible myeloid specific miR130a transgenic mice. Ectopic miR130a or miR145 expression decreased T¿RII expression in Gr1+CD11b+ cells and significantly inhibited lung metastasis. Mechanically, miRs 130a and 145 overexpression in Gr1+CD11b+myeloid cells decreased Th2 cytokine production, and increased IFNg producing CD8+ cytotoxic lymphocytes. These data suggested that miRs 130a and 145 skewed a pro-tumor toward an anti-tumor microenvironment via reprogrammed immature myeloid cells. Moreover, miRs130a and 145 also targeted insulin growth factor 1 (IGF1)/IGF1 receptor (IGF1R) signaling pathway that correlated with advanced stage in many types of cancer. IGF1R inhibitor NT157 also decreased lung metastasis via improved anti-tumor immunity. To evaluate therapeutic potentials of miRs130a and 145 mimics for lung metastasis, we used a preclinical mouse model with 4T1 mammary tumor. Systemic delivery of miRs130a and 145 enhanced efficacy of paclitaxel treatment in preclinical mouse models. Interestingly, systemic delivery of miR130a and miR145 improved anti-tumor immunity and efficacy of paclitaxel treatment. Taken together, these data suggested that miR130a and miR145 reprogramed Gr1+CD11b+ immature myeloid cells, and inhibited tumor metastasis via improvement of anti-tumor immunity. Restoration of miRs 130a and 145 functions in immature myeloid cells might be useful for reduction of tumor metastasis.

Scientific Focus Area: Cancer Biology

This page was last updated on Friday, March 26, 2021