Fig.3.

Mechanisms of resistance conferred by the MME. (A) Chemotherapeutic resistance observed in dormant cells may be conferred by the MME through E-cadherin re-expression, interactions with endothelial cells (ECs), tumor cells integrin binding to extracellular matrix (ECM), and signals, such as IL-6 and IGFs from bone marrow, contribute chemoresistance. Immune recognition and efficacy of immunotherapy is limited through downregulation of immune target molecules (e.g. PD-L1 and MHC I) and possibly some immunosuppressive effects of ECs, macrophages, myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs) which suppress the cytotoxic activity or induce apoptosis of anti-tumor T cells and NK cells. (B) Chemotherapeutic resistance observed in outgrowing metastases may be conferred through creation of dense ECM with survival signals from matricellular molecules, tenascin C in particular, and factors produced by activated stromal cells or innate immune cells. Despite upregulated expression of MHC I and PD-L1 on the tumor cells, efficacy of immunotherapy is inhibited through immunosuppressive effects of macrophages, MDSCs and regulatory T cells. Macrophages produced numerous immunosuppressive molecules, while MDCs produce inflammatory mediators which lead to apoptosis of T and NK cells. MDSCs and Tregs express immune checkpoint proteins PD-L1 and CTLA-4, respectively, which suppress effector T cells. Insulin like growth factos (IGFs); Von Willebrand factor (vWf); Indoleamine 2,3-dioxygenase (IDO); cancer –associated fibroblasts (CAFs). Made with Affinity Designer 1.7.0.