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Blockade of histamine receptor H1 augments immune checkpoint therapy by enhancing MHC-I expression in pancreatic cancer cells.
Zhong, PingShan; Nakata, Kohei; Oyama, Koki; Higashijima, Nobuhiro; Sagara, Akiko; Date, Satomi; Luo, HaiZhen; Hayashi, Masataka; Kubo, Akihiro; Wu, ChenYi; He, Shan; Yamamoto, Takeo; Koikawa, Kazuhiro; Iwamoto, Chika; Abe, Toshiya; Ikenaga, Naoki; Ohuchida, Kenoki; Morisaki, Takashi; Oda, Yoshinao; Kuba, Keiji; Nakamura, Masafumi.
Afiliación
  • Zhong P; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Nakata K; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan. nakata.kohei.678@m.kyushu-u.ac.jp.
  • Oyama K; Department of Diagnostics and Therapeutics Endoscopy, Kyushu University Hospital, Fukuoka, 812-8582, Japan. nakata.kohei.678@m.kyushu-u.ac.jp.
  • Higashijima N; Department of Overseas Exchange Center, Kyushu University Hospital, Fukuoka, 812-8582, Japan. nakata.kohei.678@m.kyushu-u.ac.jp.
  • Sagara A; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Date S; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Luo H; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Hayashi M; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Kubo A; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Wu C; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • He S; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Yamamoto T; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Koikawa K; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Iwamoto C; Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Abe T; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Ikenaga N; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Ohuchida K; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Morisaki T; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Oda Y; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
  • Kuba K; Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, 812-0018, Japan.
  • Nakamura M; Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
J Exp Clin Cancer Res ; 43(1): 138, 2024 May 08.
Article en En | MEDLINE | ID: mdl-38715057
ABSTRACT

BACKGROUND:

Although immune checkpoint blockade (ICB) therapy has proven to be extremely effective at managing certain cancers, its efficacy in treating pancreatic ductal adenocarcinoma (PDAC) has been limited. Therefore, enhancing the effect of ICB could improve the prognosis of PDAC. In this study, we focused on the histamine receptor H1 (HRH1) and investigated its impact on ICB therapy for PDAC.

METHODS:

We assessed HRH1 expression in pancreatic cancer cell (PCC) specimens from PDAC patients through public data analysis and immunohistochemical (IHC) staining. The impact of HRH1 in PCCs was evaluated using HRH1 antagonists and small hairpin RNA (shRNA). Techniques including Western blot, flow cytometry, quantitative reverse transcription polymerase chain reaction (RT-PCR), and microarray analyses were performed to identify the relationships between HRH1 and major histocompatibility complex class I (MHC-I) expression in cancer cells. We combined HRH1 antagonism or knockdown with anti-programmed death receptor 1 (αPD-1) therapy in orthotopic models, employing IHC, immunofluorescence, and hematoxylin and eosin staining for assessment.

RESULTS:

HRH1 expression in cancer cells was negatively correlated with HLA-ABC expression, CD8+ T cells, and cytotoxic CD8+ T cells. Our findings indicate that HRH1 blockade upregulates MHC-I expression in PCCs via cholesterol biosynthesis signaling. In the orthotopic model, the combined inhibition of HRH1 and αPD-1 blockade enhanced cytotoxic CD8+ T cell penetration and efficacy, overcoming resistance to ICB therapy.

CONCLUSIONS:

HRH1 plays an immunosuppressive role in cancer cells. Consequently, HRH1 intervention may be a promising method to amplify the responsiveness of PDAC to immunotherapy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Inhibidores de Puntos de Control Inmunológico Límite: Animals / Female / Humans / Male Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Inhibidores de Puntos de Control Inmunológico Límite: Animals / Female / Humans / Male Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Japón Pais de publicación: Reino Unido