Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells

Abstract

Background One of the most potent costimulatory molecules involved in the recognition and killing of tumor cells is CD80. However, its role and the molecular mechanisms regulating its expression in sporadic colorectal carcinogenesis remain elusive. Here, we provide evidence for CD80 overexpression in human colon epithelial cells derived from preneoplastic mucosa. Methods Expression of CD80 on colonic epithelial cells isolated from normal human colonic mucosa, preneoplastic and neoplastic specimens was assessed by flow cytometry. WT and CD80KO mice received azoxymethane to induce colon preneoplastic lesions and sacrificed to perform histology, flow cytometry analysis and immunohistochemistry of colonic mucosa. Some WT mice were treated with a monoclonal anti-CD80 antibody following AOM administration. Primary colon epithelial cells and CT26 cell line were used to quantify the expression of CD80 in response to pro-oxidant stimuli. Specific pharmacological inhibitors and siRNA silencing were used to inhibit MAPK pathways and STAT3. Results CD80 expression was significantly increased in colon epithelial cells of human preneoplastic lesions. In the AOM model, CD80 impairment by administration of neutralizing antibodies or use of CD80 knockout mice enhanced dysplasia development. In vitro, CD80 upregulation was induced by oxidative stress in colon cancer cells and primary colon epithelial cells. In addition, reactive oxygen species could induce CD80 expression via the JNK and p38 MAPK pathways, that activated STAT3 transcription factor in colon cancer epithelial cells. Conclusion This study provide evidence for a major role of CD80 in orchestrating immune surveillance of colon preneoplastic lesions and might help to develop novel approaches that exploit anti-tumor immunity to prevent and control colon cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1205-0) contains supplementary material, which is available to authorized users.

Transfer learning between preclinical models and human tumors identifies conserved NK cell activation signature in anti-CTLA-4 responsive tumors

“…Of note, melanoma cell lines had the highest B7 expression of all solid malignancy lines. These findings are supported by previous reports of B7.1 and B7.2 expression in several mouse tumor cell lines (melanoma and colorectal carcinomas) (Tirapu et al, 2006) and human tumor cell lines (gastric, esophageal and colorectal carcinomas) (Li et al, 1996) human colon preneoplastic epithelial cells (Marchiori et al, 2019). CD4+ T cells are inactivated upon CTLA-4 recognition of B7.…”

Reactive Oxygen Species and Antitumor Immunity—From Surveillance to Evasion

“…ROS were shown to impact the expression of the coinhibitory molecule PD-L1 in cancer cells in vitro, although no simple and direct relationship could be deduced between elevation/reduction of ROS production and modulation of PD-L1 expression [ 61 ]. On the other hand, ROS could induce the expression of the costimulatory molecule CD80 via the c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways, that activated Signal transducer and activator of transcription 3 (STAT3) transcription factor in colon cancer epithelial cells in vitro [ 62 ]. Moreover, it appears that modest generation of ROS by cancer cells can trigger hypoxia [ 63 ], which can modulate immunity by regulating the expression of co-stimulatory (CD137, OX-40) and co-inhibitory (PD-L1) molecules for T and NK cell activation [ 64 ].…”

Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

“…Using a HAdV-C5 chimera vector with the fiber knob of HAdV-B3 that bound to CD80 or CD86 instead of CAR, enhanced infection of these glioma cells. In a colon cancer cell line, oxidative stress and reactive oxygen species were able to increase the expression of CD80, however elevated CD80 levels were mainly found in preneoplastic colon mucosa biopsies [ 52 ]. In contrast to many Ad receptors, CD80 and CD86 do not localize to places that are hard to reach, like CAR, CD46, and DSG-2 in between cells ( Figure 1 ).…”

“…CD80 and CD86 are normally not expressed on epithelial cells, but on antigen presenting cells (APCs) such as dendritic cells [ 50 ]. However, some tumor cells have been shown to upregulate CD80 or CD86 [ 51 , 52 ]. Sialic acid (SA) residues are often the final residues on glycans and glycoproteins distributed all over the cell membrane [ 53 ].…”