5FU and CPT11 display opposite effects on β-catenin localization in CRC colons (S1); 5FU and CPT11 display opposite effects on MDSC accumulation and CD247 expression in the colons of CRC-mice (S2); 5FU or CPT11 chemotherapies do not alter the elevated Treg levels in spleens from CRC-mice (S3); A combined 5FU and CPT11 therapy preserves immunosuppression (S4); A schematic representation of mouse model for CRC in which MDSCs were in vivo depleted in CPT11 treated mice by Gr1 mAb administration every 3 days (S5); 5FU and CPT11 differently affect monocytic/granulocytic MDSC sensitivity to apoptosis (S6); 5FU and CPT11 treatments display opposite effects on mRNA expression levels of pro-inflammatory molecules (S7); 5FU and CPT11 treatments differently affect the immunological profile of mice exhibiting a pathology free chronic inflammation (S8).
ARTICLE ABSTRACT
Colorectal cancer is associated with chronic inflammation and immunosuppression mediated by myeloid-derived suppressor cells (MDSC). Although chemotherapy reduces tumor burden at early stages, it tends to have limited effect on a progressive disease, possibly due to adverse effects on the immune system in dictating disease outcome. Here, we show that patients with advanced colorectal cancer display enhanced MDSC levels and reduced CD247 expression and that some conventional colorectal cancer chemotherapy supports the immunosuppressive tumor microenvironment. A FOLFOX combined therapy reduced immunosuppression, whereas a FOLFIRI combined therapy enhanced immunosuppression. Mechanistic studies in a colorectal cancer mouse model revealed that FOLFIRI-like therapy including the drugs CPT11 and 5-fluorouracil (5FU) damaged host immunocompetence in a manner that limits treatment outcomes. CPT11 blocked MDSC apoptosis and myeloid cell differentiation, increasing MDSC immunosuppressive features and mouse mortality. In contrast, 5FU promoted immune recovery and tumor regression. Thus, CPT11 exhibited detrimental immunoregulatory effects that offset 5FU benefits when administered in combination. Our results highlight the importance of developing therapeutic regimens that can target both the immune system and tumor towards improved personalized treatments for colorectal cancer. Cancer Res; 74(21); 6022–35. ©2014 AACR.
