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Genetically engineered myeloid cells rebalance the core immune suppression program in metastasis

Authors: Kaczanowska, Sabina; Beury, Daniel W.; Gopalan, Vishaka; Tycko, Arielle K.; Qin, Haiying; Clements, Miranda E.; Drake, Justin; Nwanze, Chiadika; Murgai, Meera; Rae, Zachary; Ju, Wei; Alexander, Katherine A.; Kline, Jessica; Contreras, Cristina F.; Wessel, Kristin M.; Patel, Shil; Hannenhalli, Sridhar; Kelly, Michael C.; Kaplan, Rosandra N.

Online: https://www.sciencedirect.com/science/article/pii/S0092867421002373

Issue: Cell . 2021 Apr 15;184(8):2033-2052.e21.


Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.