Exosomes as Mediators of Resistance and Targets for New Therapies
Exosomes play crucial roles in survival of lymphoma cells, evasion of immune response and resistance to therapy. Poggio et al showed that exosomal PD-L1 suppressed T-cell function in lymph nodes draining tumor sites, and promoted tumor growth across different tumor types (100.). Local blockade of exosomal PD-L1, inhibited growth of tumor locally as well as at distant sites injected synchronously or at a later time to the PD-L1 block.
Tumor derived exosomes contain tumor antigens and MHC-I and MHC-II molecules allowing direct presentation and activation of CD8 and CD4 T-cells and cross presentation to T cells via transfer to antigen presenting cells (101,102) . Whether these mechanisms are also operational in DLBCL remains to be determined. Studies of exosomes have provided insights to mechanisms of resistance in DLBCL and possible targets for new therapy. Chen et al showed a dual role of tumor derived exosomes (TEX) in DLBCL (103.). DLBCL exosomes when incubated with dendritic cells (DC) resulted in increased proliferation and activation of dendritic cells. The dendritic cells were able to cause greater T cell expansion after incubation with the exosomes. Tumor derived exosomes however resulted in increased PD-1 expression and increased apoptosis of Th2 cells. They also demonstrated that the TEXs play a role in enhancing cell proliferation, invasion, migration, and angiogenesis with promotion of tumor growth in vivo. Their findings suggest a role for targeting exosome inhibition in developing new therapies for DLBCL or use of exosome derived vaccines to augment the anti-lymphoma immune response.
Koch et al demonstrated the presence of side population (SP) cells in DLBCL, which have stemness properties and are capable of propagating tumor growth (104). They showed an equilibrium of SP and non-SP cells, with no stemness properties, whereby exosome mediated Wnt signaling transformed non-SP cells to SP cells, and vice versa.
Exosomes have been shown to play a role in drug resistance of hematopoietic malignancies to therapy. Koch et al showed that after initial accumulation in the nucleus, the site of action of doxorubicin and pixantrone, these chemotherapeutic agents are exported into exosomes and then released from the cell, leading to reduced amount of drug at the site of action and development of resistance (105). They showed that inhibition of ABCA3, a protein involved in the transport of these drugs into exosomes resulted in trapping of the drugs in the nucleus and higher sensitivity to doxorubin and pixantrone.
Exosomal CD20 has also been shown to shield DLBCL cells from anti-CD20 immunotherapy providing a mechanism for evading this therapy (106). This mechanism of resistance was again attenuated by inhibition of ABCA3 which is involved in exosome biogenesis. Serial profiling of exosomal nucleic acids and/or proteins during therapy may identify more products involved in resistance and help develop a resistance signature during therapy that necessitates prompt therapy changes. It could also help guide development of new therapeutic targets.