title: Immune checkpoint regulator PD-L1 expression on tumor cells by contacting CD11b positive bone marrow derived stromal cells.
abstract: BACKGROUND
  Expression of programmed cell death ligand 1 (PD-L1) is an important process by which tumor cells suppress antitumor immunity in the tumor microenvironment. Bone marrow (BM)-derived immune cells are an important component of the tumor microenvironment. However, the link between PD-L1 induction on tumor cells and communication with BM cells is unknown.
  
  
  RESULTS
  This study demonstrates that BM cells have a direct effect in inducing PD-L1 expression on tumor cells, which contributes to the tumor cells' drug resistance. This novel discovery was revealed using a co-incubation system with BM cells and tumor cells. BM cells from wild-type C57BL6 mice and the immune-deficient mouse strains B-cell(-/-), CD28(-/-), perforin(-/-), and Rag2(-/-) but not CD11b(-/-) dramatically increased the expression of tumor cell surface PD-L1. This PD-L1 induction was dependent on CD11b-positive BM cells through direct contact with tumor cells. Furthermore, p38 signaling was activated in tumor cells after co-incubation with BM cells, whereas the expression of PD-L1 was remarkably decreased after co-culture of cells treated with a p38 inhibitor. The increase in PD-L1 induced by BM cell co-culture protected tumor cells from drug-induced apoptosis.
  
  
  CONCLUSIONS
  PD-L1 expression is increased on tumor cells by direct contact with BM-derived CD11b-positive cells through the p38 signaling pathway. PD-L1 may play an important role in drug resistance, which often causes failure of the antitumor response.
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. hnoh@mdanderson.org.
authors.forename: Hyangsoon
authors.initials: H
authors.lastname: Noh
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. jhu1@mdanderson.org.
authors.forename: Jiemiao
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. xwang19@mdanderson.org.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. xxia1@mdadnerson.org.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Xia
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. asatelli@mdanderson.org.
authors.forename: Arun
authors.initials: A
authors.lastname: Satelli
authors.affiliation: Department of Pediatrics-Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. Sli4@mdanderson.org.
authors.forename: Shulin
authors.initials: S
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D002450:Cell Communication; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D039481:CD11b Antigen; C498919:Cd274 protein, mouse; D009363:Neoplasm Proteins; D048051:p38 Mitogen-Activated Protein Kinases