title: FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression.
abstract: Immune checkpoint blockades that significantly prolonged survival of melanoma patients have been less effective on colorectal cancer (CRC) patients. Growing evidence suggested that fibroblast activation protein-alpha (FAP) on cancer associate fibroblasts (CAFs) has critical roles in regulating antitumor immune response by inducing tumor-promoting inflammation. In this study, we explored the roles of FAP in regulating the tumor immunity and immune checkpoint blockades resistance in CRC experimental systems. We found that CAFs with high FAP expression could induce immune checkpoint blockade resistance in CRC mouse model. Mechanistically, CAFs with high FAP expression promoted immunosuppression in the CRC tumor immune microenvironment by up-regulating CCL2 secretion, recruiting myeloid cells, and decreasing T-cell activity. In human CRC samples, FAP expression was proportional to myeloid cells number, but inversely related to T-cell number. High FAP expression also predicted poor survival of CRC patients. Taken together, our study suggested that high FAP expression in CAFs is one reason leading to immune checkpoint blockades resistance in CRC patients and FAP is an optional target for reversing immune checkpoint blockades resistance.
authors.affiliation: Department of Clinical Laboratory, Linyi Central Hospital, Shandong Province, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Clinical Laboratory, Linyi Central Hospital, Shandong Province, China.
authors.forename: Xiangting
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Department of Clinical Laboratory, Linyi Central Hospital, Shandong Province, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Clinical Neurosurgery, Linyi Central Hospital, Shandong Province, China. Electronic address: ling2chen2099@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: He
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology; D010450:Endopeptidases; D005347:Fibroblasts / Q000276:immunology*; D018093:Gelatinases / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D012697:Serine Endopeptidases / Q000276:immunology*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: CCL2; Cancer-associated fibroblast; Colorectal cancer; Fibroblast activation protein-alpha; Immune checkpoint blockade