Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 69, Issue 6, Pages 1001-1014Publisher
SPRINGER
DOI: 10.1007/s00262-020-02520-z
Keywords
PD-1 (programmed death-1); PD-L1 (programmed death-ligand 1); Immune checkpoint blockade; Hematological malignancies; CRISPR; Cas9
Categories
Funding
- Fondo de Investigaciones Sanitarias, Ministry of Health, Spanish Government [1300029]
- European Union ERDF/ESF, Investing in your future
- Unit of Excellence Research UIC (Department of Education of the Regional Government, Junta de Castilla y Leon) [012]
- Gerencia Regional de Salud [BIO/01/15, GRS963/A/2014, GRS1142/A/2015, GRS 1505/A/2017]
- Miguel Servet National Grant (Health National Organization Research) (Instituto de Salud Carlos III) [CP12/03063, CPII17/00002, FIS PI16/00002]
- National Network CIBER-ONC (oncology research) [CB16/12/00480]
- [LE093U13]
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The expression of PD-L1 on tumor cells or within the tumor microenvironment has been associated with good prognosis and sustained clinical responses in immunotherapeutic regimens based on PD-L1/PD-1/CD80 immune checkpoint blockade. To look into the current controversy in cancer immunotherapy of the relative importance of PD-L1 expression on tumor cells versus non-tumor cells of the tumor microenvironment, a hematological mouse tumor model was chosen. By combining a genetic CRISPR/Cas9 and immunotherapeutic approach and using a syngeneic hematopoietic transplantable tumor model (E.G7-cOVA tumor cells), we demonstrated that dual blockade of PD-L1 interaction with PD-1 and CD80 enhanced anti-tumor immune responses that either delayed tumor growth or led to its complete eradication. PD-L1 expression on non-tumor cells of the tumor microenvironment was required for the promotion of tumor immune escape and its blockade elicited potent anti-tumor responses to PD-L1 WT and to PD-L1-deficient tumor cells. PD-L1(+) tumors implanted in PD-L1-deficient mice exhibited delayed tumor growth independently of PD-L1 blockade. These findings emphasize that PD-L1 expression on non-tumor cells plays a major role in this tumor model. These observations should turn our attention to the tumor microenvironment in hematological malignancies because of its unappreciated contribution to create a conditioned niche for the tumor to grow and evade the anti-tumor immune response.
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