Ngar-Woon Kam

and 9 more

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.