Intratumoral STING activations overcome negative impact of cisplatin on antitumor immunity by inflaming tumor microenvironment in squamous cell carcinoma

Although cisplatin (CDDP) has been used as a major chemotherapeutic drug for head and neck squamous cell carcinoma (HNSCC), its impact on T-cell functions is controversial. Therefore, we investigated the immunologic effects of CDDP and antitumor effects by combination therapy of CDDP with a ligand f...

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Veröffentlicht in:Biochemical and biophysical research communications Jg. 522; H. 2; S. 408 - 414
Hauptverfasser: Harabuchi, Shohei, Kosaka, Akemi, Yajima, Yuki, Nagata, Marino, Hayashi, Ryusuke, Kumai, Takumi, Ohara, Kenzo, Nagato, Toshihiro, Oikawa, Kensuke, Ohara, Mizuho, Harabuchi, Yasuaki, Ohkuri, Takayuki, Kobayashi, Hiroya
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Elsevier Inc 05.02.2020
Schlagworte:
Animals
antineoplastic activity
Cell Line, Tumor
Cell Proliferation - drug effects
Chemokines - metabolism
Cisplatin
Cisplatin - pharmacology
Cisplatin - therapeutic use
Combination therapy
Combined Modality Therapy
dose response
Drug Synergism
drug therapy
genes
guanosine
head and neck squamous cell carcinoma
Humans
Immunity - drug effects
immunotherapy
Inflammation - pathology
interferons
ligands
Lymphocyte Activation - drug effects
Lymphocytes, Tumor-Infiltrating - drug effects
Lymphocytes, Tumor-Infiltrating - immunology
Membrane Proteins - metabolism
mice
Mice, Inbred BALB C
monoclonal antibodies
Nucleotides, Cyclic
Squamous cell carcinoma
Squamous Cell Carcinoma of Head and Neck - drug therapy
Squamous Cell Carcinoma of Head and Neck - immunology
Squamous Cell Carcinoma of Head and Neck - pathology
STING
T-lymphocytes
Tumor Microenvironment - drug effects
Tumor Microenvironment - immunology
CXCL
Squamous cell carcinoma
dLNs
Combination therapy
PBMC
TME
Cisplatin
mAb
IFN
MDSCs
CDDP
SCC
cGAMP
HDs
HNSCC
PD-L1
STING
CXCR
TILs
PD-1
ISSN:0006-291X, 1090-2104, 1090-2104
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Zusammenfassung:Although cisplatin (CDDP) has been used as a major chemotherapeutic drug for head and neck squamous cell carcinoma (HNSCC), its impact on T-cell functions is controversial. Therefore, we investigated the immunologic effects of CDDP and antitumor effects by combination therapy of CDDP with a ligand for stimulator of interferon genes, cyclic guanosine monophosphate-adenosine monophosphate (cGAMP). Direct impacts of CDDP on T-cell functions were addressed by comparing T-cell functions between human subjects treated and untreated with CDDP. The immune responses and the efficacy of combination therapy using CDDP and cGAMP were assessed using BALB/c mice inoculated with mouse squamous cell carcinoma (SCC) cell lines. CDDP inhibited T-cell proliferation in a dose-dependent manner. T-cell functions of CDDP-treated HNSCC patients were comparable to those of healthy donors and CDDP-untreated HNSCC patients. In the mice bearing SCC cell lines, combination therapy using CDDP and cGAMP enhanced the gene expressions of CXCL9 and CXCL10 in the tumor tissues and inhibited tumor growth. The antitumor effect was cancelled by anti-CXCR3 monoclonal antibody. These findings suggest that the combination therapy using CDDP and an immunomodulating drug like cGAMP would be a rational cancer immunotherapy for patients with HNSCC. •T-cell functions of the patients treated with cisplatin are comparable to those of the healthy donors.•Intratumoral administration of cGAMP upregulates gene expressions of CXCL9 and CXCL10 in the tumor site.•Combination of CDDP and cGAMP shows antitumor effect in mice bearing squamous cell carcinoma.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0006-291X
1090-2104
1090-2104
DOI:10.1016/j.bbrc.2019.11.107