Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer
| Autor: | Alvaro Padron, Srilakshmi Pandeswara, Ratna K. Vadlamudi, Vincent Hurez, Bin Yuan, Rong Li, Curtis A. Clark, Jose R. Conejo-Garcia, Harshita Gupta, Gangadhara R. Sareddy, Tyler J. Curiel |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Homeobox protein NANOG Cancer Research medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities Biology medicine.disease_cause Article 03 medical and health sciences 0302 clinical medicine Interferon PD-L1 Internal medicine mental disorders Genetics medicine PI3K/AKT/mTOR pathway Melanoma medicine.disease 030104 developmental biology 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein Ovarian cancer Carcinogenesis human activities medicine.drug |
| Zdroj: | Signal Transduction and Targeted Therapy |
| ISSN: | 2059-3635 2095-9907 |
| Popis: | As tumor PD-L1 provides signals to anti-tumor PD-1+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor-initiating cells (TICs) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TICs express more PD-L1 versus non-TICs. Silencing 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 vivo. Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, 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. The tumor-cell signaling molecule PD-L1 promotes self-renewal tumor initiating cells (TICs) in melanoma and ovarian cancer. PD-L1 is known to help cancer cells evade the immune response by inhibiting T-cell activity. Now, Tyler Curiel at the University of Texas Health Science Center at San Antonio and colleagues show that PD-L1 has important effects on cancer cells themselves. They found that PD-L1 increases the number of treatment-resistant TICs in mouse and human cancer cell lines by stimulating the expression of genes associated with long-term self-renewal. Interestingly, it also sensitizes these cells to the anti-cancer action of interferon-? and rapamycin. These findings highlight differences between TICs and differentiated tumor cells, which could explain their distinct responses to treatment. Further understanding the effects of PD-L1 signaling will contribute to the development of more effective therapeutic strategies. |
| Databáze: | OpenAIRE |
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