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

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.
Competing Interests: Declaration of interests S.K., D.W.B., H.Q., and R.N.K. are inventors on international patent application no. PCT/US2020/17515, “Genetically modified hematopoietic stem and progenitor cells (HSPCs) and mesenchymal cells as a platform to reduce or prevent metastasis, treat autoimmune and inflammatory disorders, and rebalance the immune milieu and dysregulated niches.” The remaining authors have no competing interests. Inclusion and diversity One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. One or more of the authors of this paper self-identifies as living with a disability. One or more of the authors of this paper self-identifies as a member of the LGBTQ+ community.
(Published by Elsevier Inc.)