Abstract
Triple-negative breast cancer (TNBC) is an aggressive disease with poor prognosis and limited therapeutic options. Recent advances in the immunotherapy field have enabled the development of new treatment strategies, among which the use of bispecific antibodies (BsAbs), able to redirect T cells against tumors, has shown promising results. In particular, a BsAb that uses TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2) as a target was constructed and demonstrated good results in redirecting CD3+ T cells to kill TRAIL-R2-expressing TNBC cells. In the present study, we investigated whether treatment with selinexor, a selective inhibitor of nuclear export (SINE) targeting exportin-1/chromosome maintenance protein 1 (XPO1/CRM1), could potentiate the antitumor activity of this BsAb. In combination experiments, we found that selinexor-exposed TNBC cells exhibited greater growth inhibition when treated with the TRAIL-R2xCD3 BsAb than that expected by simple additivity. Similarly, the apoptosis rate in selinexor/TRAIL-R2xCD3 BsAb-treated TNBC cells was significantly higher than that observed after exposure to either single agent. Together, our results suggest that the combination of selinexor and TRAIL-R2xCD3 BsAb can be a viable anticancer strategy and indicate this treatment as a promising therapeutic option for TNBC patients.
Highlights
Despite ongoing surveillance by T cells and other components of the immune system, tumors develop in the presence of an intact immune system
To a variable extent, TRAIL-R2 expression was present in three cell lines (SUM-159 > MDA-MB-231 > MS-186), it was not detected in MDA-MB-468 cells (Figure 1a and Supplementary Figure S1)
We proposed the combination of a bispecific antibodies (BsAbs) able to retarget T cells to kill
Summary
Despite ongoing surveillance by T cells and other components of the immune system, tumors develop in the presence of an intact immune system. The TRAIL-R2xCD3 BsAb that we had developed, despite poor ability to activate the extrinsic apoptotic pathway as well when multimerized by crosslinkers, was able to efficiently redirect activated T-cells and led to killing of TRAIL-R2+ tumor cells by perforin and granzyme. This BsAb demonstrated a wide range of activity against tumors of different origins including triple-negative breast carcinoma (TNBC) [6]. Antitumor response was efficient against all tested tumor cell lines, the activity of the BsAb could be further improved by combining it with other molecules able to sensitize cells by acting on the TRAIL-R2 pathway
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