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.