Idronoxil combined with cisplatin rescues refractory immune response in
nasopharyngeal carcinoma
Abstract
Background. Nasopharyngeal carcinoma is a chemosensitive cancer
characterized by prominent lymphocytic infiltration. However, recurrence
remains a major challenge in treating this disease. Here, we examined
the effects of idronoxil (IDX) on tumor-lymphocyte interactions. Methods
The antitumor activity of cisplatin and/or IDX was tested in authentic
EBV-positive NPC-derived cell lines (C666, C17 and NPC43). We analyzed
2D monolayer and 3D spheroids cocultures of NPC cell lines with immune
cells to assess the infiltration, activation, phenotype and function of
T cells toward human nasopharyngeal tumors in vitro. Flow cytometric and
immunohistochemical analyses were carried out to evaluate infiltrating T
cells in subcutaneous mice models. Results. Administration of low-dose
of IDX (1-2 µM) not only sensitizes cancer cells to chemotherapy via
apoptosis, but also promotes T cell proliferation and cytotoxicity. More
importantly, combination treatment of IDX and cisplatin in cancer cells
can enhance the expansion, trafficking and priming of CD4+, CD8+ and
double-positive (DP) T cells. Mechanistically, we showed that the
increase in migratory DP T cells was largely mediated by the CXCL10/type
I interferon (IFN) axis, where IDX precipitates an elevation in IFNα
levels and leads to CXCL10 induction. Additionally, IDX enhanced T-cell
infiltration towards tumor spheroids with acquisition of increased
tissue homing and functional abilities (attenuated CD62L and PD1
expression). Conclusions. Our findings underscore the potential of IDX
to induce immunomodulatory responses, and in combination with
conventional chemotherapies, enhance antitumor immunity.