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Tumor cell-intrinsic PD-L1 promotes tumor-initiating cellgeneration and functions in melanoma and ovarian cancer

Signal Transduction and Targeted Therapy 2016年第1期1卷 1-9页

作者： Harshita B Gupta Curtis A Clark Bin Yuan gangadhara Sareddy Srilakshmi pandeswara Alvaro S padron Vincent Hurez jose Conejo-garcia Ratna Vadlamudi Rong Li Tyler J Curiel department of Medicine University of Texas Health Science CenterSan AntonioTXUSA The Graduate School of Biomedical Sciences University of Texas Health Science CenterSan AntonioTXUSA department of Molecular Medicine University of Texas Health Science CenterSan AntonioTXUSA department of Obstetrics and Gynecology University of Texas Health Science CenterSan AntonioTXUSA Tumor Microenvironment and Metastasis Program The Wistar InstitutePhiladelphiaPAUSA cancer Therapy and Research Center University of Texas Health Science CenterSan AntonioTXUSA department of Microbiology and Immunology University of Texas Health Science CenterSan AntonioTXUSA

As tumor PD-L1 provides signals to anti-tumor PD-1^(+)T cells that blunt their functions,αPD-1 andαPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling ***,tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals,among other important ***-initiating cells(TICs)generate carcinomas,resist treatments and promote *** show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells,TICs express more PD-L1 versus *** PD-L1 in B16 and ID8agg cells by shRNA(‘PD-L1lo’)reduced TIC numbers,the canonical TIC genes nanog and pou5f1(oct4),and functions as assessed by tumorosphere development,immune-dependent and immune-independent tumorigenesis,and serial transplantability in ***,tumor PD-L1 sensitized TIC to interferon-γand rapamycin in ***-intrinsic PD-L1 similarly drove functional TIC generation,canonical TIC gene expression and sensitivity to interferon-γand rapamycin in human ES2 ovarian cancer ***,tumor-intrinsic PD-L1 signals promote TIC generation and virulence,possibly by promoting canonical TIC gene expression,suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses.

关键词： melanoma interferon initiating

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