Modulation of immune and stromal cells by cancer immunotherapy and chemotherapy in mice.
In: Student Reports, Summer 2017, Jackson Laboratory
Dr. Gary Ren
The tumor microenvironment is composed of both stromal and immune cells that interact with each other to either support or suppress tumor progression. Although current anti-cancer therapies have significantly improved the survival of cancer patients, they have also been reported to be associated with post-therapy early relapse and acquired resistance. It is believed that cancer therapies always cause host tissue damages which trigger the damage repairing mechanisms by stromal cell and immune cells through overexpression of cytokines and trophic factors. We comprehensively analyzed the localized immune and stromal cell populations in the lung, liver, bone marrow (BM), spleen, and peripheral blood (PB) in post-immunotherapy and post-chemotherapy immunocompetent mice. It was demonstrated that, although anti-PD1 /antiCTLA4 combination immunotherapy indeed systemically stimulated T-cell activation, it also lead to increased Tim3+ PD-1+ exhausted T cells accompanied by loss of na'lve T cell pool. Moreover, immunotherapy also significantly accelerated infiltration of inflammatory myeloid cell within the lung and liver. In our chemotherapy experiment, paclitaxel treatment was shown to stimulate BM and splenic hematopoiesis as well as increased monocyte and T-cell infiltration within the lung. In vitro, paclitaxel-pretreated lung mesenchymal cells (LMCs) seemed to selectively adhere conventional monocytes and macrophages, as well as suppressing CD4+ T cell proliferation when compared to untreated LMCs. Our results indicated that upon cancer therapy treatment, tissue stromal cells may acquire functional changes in modulating host innate and adaptive immune cells. By further performing functional measurement of posttherapy host microenvironment in regulating tumor progression, our stUdies may help understand the mechanisms underlying the post therapy early metastasis in many cancer patients. Our research goal is to develop novel stromal cell and myeloid cell-targeting strategies to improve the efficacy of current cancer therapeutics.
Hayes, Kevin, "Modulation of immune and stromal cells by cancer immunotherapy and chemotherapy in mice." (2017). Summer and Academic Year Student Reports. 2570.