Immune-Dependent and Independent Antitumor Activity of GM-CSF Aberrantly Expressed by Mouse and Human Colorectal Tumors

Abstract

Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematologic compartment that may enhance antitumor immune responses, mainly by activation of dendritic cells. Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM-CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune-associated antitumor effect. Unexpectedly, an immune-independent antitumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy.

GM-CSF Production by Tumor Cells Is Associated with Improved Survival in Colorectal Cancer

“…Most recently however, immune-dependent and immune-independent antitumor activities of GM-CSF in human colorectal cancer have been suggested (38). In a group of 124 patients, association with favorable prognosis was detectable in 8 patients bearing tumors concomitantly expressing genes encoding GM-CSF and both receptor subunits (38).…”

“…In a group of 124 patients, association with favorable prognosis was detectable in 8 patients bearing tumors concomitantly expressing genes encoding GM-CSF and both receptor subunits (38). However, MMR status of colorectal cancer was not analyzed, GM-CSF protein expression was not investigated and the association with macrophage and T-cell infiltration or with the expression of additional cytokines promoting their polarization was not explored.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…G-CSF is ectopically expressed in several human tumors such as leukemia [172], bladder [173], pancreatic [174], cervical [175], ovarian [176], head and neck [177], colorectal [178] and breast carcinoma [179]. Similarly, some human cancers show elevated GM-CSF expression levels [31,180,181]. It is therefore not surprising that elevated numbers of circulating neutrophils are seen in a wide variety of human malignancies.…”

A plant-made cholera toxin B subunit enhances mucosal wound healing and protects against ulcerative colitis and colon cancer.

“…Ifnγ, Csf2 and Tgfβ1) (165)(166)(167). Mice were injected with AOM one week prior to the first round of DSS exposure.…”

“…5.3 Other cytokines essential to the inhibition of tumor growth were also altered by CTBp administration. For example, IFNγ, IL-2 and GM-CSF have been shown to suppress colon cancer progression (165,166,174,175) and the two former cytokines were significantly induced while the latter was reduced by…”