Mycotoxins modulate oxaliplatin-induced phagocytosis of human colon cancer cells through oxidative stress in vitro.

Phagocytosis of cancer cells is pivotal in the anticancer immune response. To evade phagocytosis, tumor cells express "don't eat me" signals or inhibit "eat me" signals. This can be overcome by the anticancer drug oxaliplatin, which induces "eat me" signals. However, not only anticancer therapies modulate the immune response, but prevalent mycotoxins can also stimulate or suppress immune functions. Consequently, the question arises whether immunomodulating mycotoxins affect the ability of cancer cells to evade phagocytosis and modulate oxaliplatin-induced phagocytosis. Phagocytosis of colon cancer cells treated with oxaliplatin (10-100 µM), alternariol (5-20 µM), deoxynivalenol (1-4 µM), ochratoxin A (OTA) (10-40 µM), or zearalenone (ZEN) (10-40 µM) by immature dendritic cells (DCs) generated from peripheral blood mononuclear cells or THP-1 monocytes was assessed by fluorescence staining and flow cytometry. Expression of "eat me" (calreticulin and phosphatidylserine) and "don't eat me" signals (CD47 and PDL1) was investigated by flow cytometry. In addition, cell surface patterns in the form of high-mannose N-glycans were analyzed by flow cytometry, and oxidized phospholipids by using fluorescent probes and malondialdehyde content. Our results showed that OTA, ZEN (> 20 µM), and oxaliplatin (> 50 µM) increased phagocytosis of cancer cells, with OTA and ZEN further enhancing oxaliplatin-induced stimulation. This was mainly associated with increased reactive oxygen species and upregulation of oxidized phospholipid patterns. In conclusion, mycotoxin contamination might (over-)stimulate cancer cell phagocytosis by inducing oxidative stress, thereby altering the anticancer immune response. While this might improve therapy outcomes, possible immune exhaustion or tolerogenic phagocytosis might also aggravate them.