Open AccessProgrammed cell death ligand 1 d isruption by clustered regularly interspaced short palindromic repeats /Cas9‐genome editing promotes antitumor immunity and suppresses ovarian cancer progression
Author(s) -
Yahata Tamaki,
Mizoguchi Mika,
Kimura Akihiko,
Orimo Takashi,
Toujima Saori,
Kuninaka Yumi,
Nosaka Mizuho,
Ishida Yuko,
Sasaki Izumi,
FukudaOhta Yuri,
Hemmi Hiroaki,
Iwahashi Naoyuki,
Noguchi Tomoko,
Kaisho Tsuneyasu,
Kondo Toshikazu,
Ino Kazuhiko
Publication year - 2019
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13958
Subject(s) - ovarian cancer , tumor necrosis factor alpha , tumor microenvironment , ovarian tumor , cancer research , biology , cancer , immune system , immunology , genetics
Programmed cell death ligand 1 ( PD ‐L1) on tumor cells suppresses anti‐tumor immunity and has an unfavorable prognostic impact in ovarian cancer patients. We herein report the pathophysiological and therapeutic impacts of PD ‐L1 disruption in ovarian cancer. PD ‐L1 was genetically disrupted in the murine ovarian cancer cell line ID 8 using clustered regularly interspaced short palindromic repeats ( CRISPR )/Cas9‐mediated genome editing. PD ‐L1 knockout ( KO ) and control ovarian cancer cells were intraperitoneally inoculated into syngeneic mice, and survival and tumor dissemination were evaluated. Survival times were significantly longer in the PD ‐L1‐ KO ID 8‐inoculated groups than in their control groups, and its therapeutic benefit was enhanced in combination with the cisplatin treatment. Tumor weights and ascites volumes were significantly lower in the PD ‐L1‐ KO ID 8 groups than in their control groups. Immunohistochemical and immunofluorescence analyses showed that intratumoral CD 4 + T cells, CD 8 + T cells, NK cells and CD 11c + M1 macrophages were significantly increased, whereas regulatory T cells were significantly decreased in the PD ‐L1‐ KO ID 8 groups compared with those in their control groups. The intratumoral mRNA expression of interferon‐γ, tumor‐necrosis factor‐α, interleukin ( IL )‐2, IL ‐12a, CXCL 9 and CXCL 10 was significantly stronger, while that of IL ‐10, vascular endothelial growth factor, CXCL 1 and CXCL 2 was significantly weaker in the PD ‐L1‐ KO ID 8 groups. These results indicate that CRISPR /Cas9‐mediated PD ‐L1 disruption on tumor cells promotes anti‐tumor immunity by increasing tumor‐infiltrating lymphocytes and modulating cytokine/chemokine profiles within the tumor microenvironment, thereby suppressing ovarian cancer progression. These results suggest that PD ‐L1‐targeted therapy by genome editing may be a novel therapeutic strategy for ovarian cancer.