Figure 3. The expression of inhibitory immune checkpoint
receptors on CD8+ T-cells [38].
Extracellular vesicles
Extracellular vesicles (EVs) are membrane-bound organelles that are
released from all cells to the extracellular space and biological
fluids, e.g., blood. They can contain molecular cargo (e.g., RNA,
protein and metabolites) and carry cell-specific markers on their
surface, which unveils their cell of origin. In recent years, the focus
on EVs and their role in oncogenesis, metastatic disease and resistance
to cancer therapy has expanded [42]. Caivano et al . showed
that many patients with haematological malignancies, including MM, had a
significantly higher amount of EVs in peripheral blood (PB) compared to
healthy individuals. Most EVs from the haematological patients expressed
a cancer antigen specific for the individual disease on their surface.
EVs from MM patients expressed CD38 [43]. The MM bone marrow
microenvironment is a complex network of several different cell types,
and EVs may contribute to the cross talk between malignant and
non-malignant cells. Multiple studies in different types of cancer
suggest that EVs may play a role in drug-resistance by several different
mechanisms. For example by suppression of immune cells, by transferring
drug-efflux pumps from drug-resistant cells to drug-sensitive cells, or
by binding therapeutic mAbs in the circulation and thereby preventing
them from reaching their target [44]. In vivo studies have revealed
that lenalidomide-resistance can be transmitted from resistant to
non-resistant MM cells via EVs [45]. Breast carcinoma cells, which
express human epidermal growth factor receptor 2 (HER2), can be treated
with trastuzumab, a mAb like DARA. These carcinoma cells secrete EVs
expressing HER2, which then binds trastuzumab off target and inhibits
the interaction of trastuzumab with the tumour cells [46]. The same
process of capturing and neutralizing a therapeutic antibody has been
observed with rituximab in lymphoma [47]. In line with the findings
of HER2 expressing cells in breast cancer and CD20 expressing cells in
lymphomas, an in vitro study has revealed that DARA treated MM cell
lines secrete EVs expressing a CD38/daratumumab complex [48].
Likewise, EVs isolated from MM patients receiving DARA express CD38
[49]. Brennan et al. performed mass spectrometry on EVs from PB of
10 DARA treated patients (5 responding to DARA and 5 progressing on
DARA) and 10 untreated healthy control EV samples. The majority of
peptides identified in both the DARA treated MM EVs and healthy control
EVs matched the DARA sequence. This is due to the fact that DARA is a
fully human IgG. But in 9 out of 10 patients treated with DARA, they
found EVs containing a peptide sequence that was not detected in the 10
control samples, with several MM patients having multiple DARA-specific
peptides. This finding supports the hypothesis that DARA is present on
EVs from patients treated with DARA and thus bound off target. Whether
the binding of DARA off target contributes to the development of
resistance is not known. In addition, the expression of the CIPs CD55
and CD59 was higher on EVs isolated from DARA treated MM patients
compared to healthy controls [49]. In combination with the high
amounts of CD55 and CD59 on the plasma membrane of the myeloma cells
this may inhibit CDC mediated by DARA [23].
Conclusion
DARA has improved the treatment of myeloma patients significantly, but
patients relapsing on DARA is still a clinical challenge. It seems that
a high expression of CD38 on malignant plasma is essential for the
initial response, but might be a disadvantage for the long-term
response. The immune checkpoint receptor TIGIT is highly expressed on
CD8+ T-cells from myeloma patients, but has not proved its importance in
the clinical setting yet. Whether exhaustion of T-cells is important for
the development of resistance to DARA is still not known. Furthermore,
the formation of circulating EVs binding DARA off target, could
potentially contribute to this development. Further research is needed.
Conflicts of interest
The author declares no conflicts of interest.
Acknowledgements
This focused review is based on the PhD thesis Resistance to daratumumab
in patients with multiple myeloma [50].
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