Exosomal PD-L1 from ovarian carcinoma promotes CD8+ T cell dysfunction via PI3K/AKT/mTOR inhibition and facilitates cisplatin resistance

Background Cisplatin resistance is a problem for the clinical treatment of ovarian cancer. The basic path by which cancer-secreted exosomal PD-L1 modifies the immune environment to promote chemoresistance is not known. This study investigated how ovarian carcinoma exosomal PD-L1 promotes CD8 + T cell dysfunction and cisplatin resistance. Methods SKOV3-originating exosomes were used to study uptake by CD8 + T cells, PD-1 expression, phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, and dysfunction markers, both in the presence and absence of exosomal PD-L1 silencing. Mice bearing tumours were treated in vivo with either cisplatin alone or in combination with SKOV3 exosomes/shPD-L1 exosomes, and then tumour expansion, cisplatin efficacy, exhausted T cell ratios and PI3K/AKT/mTOR activation in isolated tumour CD8 + T cells were assessed. Results Ovarian cancer-derived vesicles carrying PD-L1 were taken up by CD8 + T cells and were associated with increased PD-1 expression and impaired effector function. In vitro, SKOV3-derived vesicles increased cisplatin tolerance in SKOV3 cells, whereas in the xenograft experiment they were associated with reduced cisplatin tumor-growth inhibition; both effects were attenuated when vesicles were derived from PD-L1-silenced cells. The exosome group had more exhausted T cells, and tumor-derived CD8 + T cells showed reduced PI3K/AKT/mTOR signalling; shPD-L1 restored this signalisation. The study demonstrates parallel associations of SKOV3-derived vesicles with CD8 + T-cell dysfunction and tumor-cell cisplatin tolerance; it does not establish that the immune phenotype causes the tumor-cell-autonomous resistance observed in vitro. Conclusion ovarian cancer exosomes deliver PD-L1 to tumour-resident CD8 + T cells, inhibit the PI3K/AKT/mTOR pathway to induce T cell dysfunction, thereby fostering an immunosuppressive microenvironment that supports cisplatin resistance. These preclinical findings identify exosomal PD-L1 as a candidate contributor to CD8 + T-cell dysfunction and reduced cisplatin sensitivity, warranting validation in immunocompetent or humanized models and patient-derived samples.