biostudies-literature00570Shima TPublic Trust Fund for Clinical Cancer ResearchPrincess Takamatsu Cancer Research FundTakeda Science FoundationKeio Gijuku Academic Development FundsJapan Society for the Promotion of Science727-738https://www.ebi.ac.uk/biostudies/studies/S-EPMC7004546biostudies-literatureUnknown111(2)Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8⁺ cytotoxic T cells and FoxP3⁺ regulatory T cells. Among these immune cells, TAM and CD8⁺ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8⁺ T cells are known to induce tumor PD-L1 expression via interferon-? production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8⁺ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-? inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.Cancer scienceInfiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma.PMC700454616K0871917K16617Shigenobu TIwasaki THayashi YShimoda MAsamura HAbe TShima TOhtsuka TKanai YEmoto KNishimura T57falseInfiltration of tumor-associated macrophages is involved in tumor programmed death-ligand 1 expression in early lung adenocarcinoma.Programmed death-ligand 1 (PD-L1) is an immune modulator that promotes immunosuppression by binding to programmed death-1 of T-lymphocytes. Although tumor cell PD-L1 expression has been shown to be associated with the clinical response to anti-PD-L1 antibodies, its concise regulatory mechanisms remain elusive. In this study, we evaluated the associations of tumor PD-L1 expression and immune cell infiltrating patterns in 146 cases of early lung adenocarcinoma (AC) to investigate the possible extrinsic regulation of tumor PD-L1 by immune cells. Using immunohistochemistry, cell surface PD-L1 expression in tumor cells was observed in 18.5% of stage 0-IA lung AC patients. Tumor PD-L1 positivity was significantly associated with stromal invasion, which was accompanied by increased tumor-associated macrophages (TAM), CD8⁺ cytotoxic T cells and FoxP3⁺ regulatory T cells. Among these immune cells, TAM and CD8⁺ T cells significantly accumulated in PD-L1-positive carcinoma cell areas, which showed a tumor cell nest-infiltrating pattern. Although CD8⁺ T cells are known to induce tumor PD-L1 expression via interferon-? production, the increased TAM within tumors were also associated with tumor cell PD-L1 positivity, independently of CD8⁺ T cell infiltration. Our in vitro experiments revealed that PD-L1 expression in lung cancer cell lines was significantly upregulated by co-culture with M2-differentiated macrophages; expression of PD-L1 was reduced to baseline levels following treatment with a transforming growth factor-? inhibitor. These results demonstrated that tumor-infiltrating TAM are extrinsic regulators of tumor PD-L1 expression, indicating that combination therapy targeting both tumor PD-L1 and stromal TAM might be a possible strategy for effective treatment of lung cancer.2020-01-01T00:00:00Z2020 Feb2021-02-21T10:58:03Z2020-05-22T10:07:14ZS-EPMC70045463182166510.1111/cas.14272