Fig. 2: Contributions of non-hematopoietic cells in the bone marrow niche to AML immune escape.

Representative mechanisms by which AML-reprogrammed niche cells can promote immune evasion. Mesenchymal stromal cells (MSCs) can regulate the immune response in the leukemic BM microenvironment by secreting a plethora of inhibitory factors, as soluble molecules or as a component of exosomes (1). These factors can inhibit cell proliferation, cytolysis, and production of anti-leukemia cytokines by effector lymphocytes. MSCs mainly through the altered production of CXCL12, interacting with CXCR4, can influence the fate of leukemic cells by triggering their proliferation, spread, and survival and regulate leukocyte migration to the BM niche (2). MSCs and adipocytes regulate the leukemia cells’ metabolism (3). The mitochondrial transfer has recently been appreciated to be a mechanism of intercellular communication associated with chemoresistance and potentially also with immune resistance. Tunneling nanotubules (TNTs) appear to be the primary exchange route used by MSCs to donate mitochondria to AML blasts, boosting oxidative phosphorylation and consequently ROS production which is used by AML blasts as a strategy to evade anti-leukemic effector lymphocytes. A reciprocal relationship occurs between AML blasts and adipocytes wherein malignant cells induce lipolysis from adipocytes and, in turn, adipocytes release fatty acids, which are used as an energy source by malignant hematopoietic cells. Fatty acid oxidation seems to promote the development and activity of immunosuppressive immune cells, such as Tregs and M2 macrophages. The dramatic increase in BM vascular permeability and decrease of blood flow that coincides with leukemic growth can alter the ability of T cells to home, adhere, and extravasate into the leukemic reservoir (4). Figure created with Biorender.