fig3

Figure 3. Features of EVs influencing NHL treatments include CD19, CD20, CD47, interleukin-12 (IL-12), programmed death-ligand 1 (PD-L1), doxorubicin, and chimeric antigen receptors (CARs)^{[41,76,85-98]}. (A) CD20+ EVs impede rituximab: CD20 antigens on EVs from NHL B cells act as a sink for rituximab. Instead of interacting with CD20 antigens on NHL B cells for antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, the monoclonal antibodies are intercepted by CD20+ EVs for a reduction in rituximab efficacy^[41,76,85]. (B) CD47+ EVs with DOX avoid macrophage phagocytosis: CD47 is ubiquitously expressed on the surface of membranes and signals macrophages not to initiate phagocytosis. It interacts with the signal regulatory protein alpha (SIRP) on the surface of macrophages for inhibitory downstream signaling of phagocytosis^[86]. Doxorubicin (DOX) enclosed within EVs has better uptake and potency than free DOX^[87]. (C) CAR-T detractors: CD19 on EVs may stimulate CAR-T cells without any NHL B cells in the vicinity, leading to premature CAR-T cell exhaustion and reduced efficacy^[88]. PD-L1 on EVs inhibits CAR-T cell activity and diminishes apoptosis of NHL B cells by reducing efficacy of CAR-T cells^[89,90]. (D) CAR-T enhancers: CD19 on EVs stimulates the release of cytotoxic granzymes from CAR-T cells for apoptosis of nearby NHL B cells^[91]. Interleukin-12 on the surface of EVs elicits interferon gamma cytokines from the same CAR-T cells for enhanced apoptosis of NHL B cells^[92]. EVs from CAR-T cells also have the chimeric antigen receptor and the Fas ligand intact from CAR-T cells^[93]. This enables CAR EVs to induce apoptosis in NHL B cells as well^[94-98] (images in the figure are not drawn to exact scale).