Accumulation of exhausted CD8+ T cells in extramammary Paget's disease

Natsuko Iga, Atsushi Otsuka, Yosuke Yamamoto, Chisa Nakashima, Tetsuya Honda, Akihiko Kitoh, Saeko Nakajima, Gyohei Egawa, Takashi Nomura, Teruki Dainichi, Shigeto Matsushita, Hideaki Tanizaki, Yuki Yamamoto, Takeru Funakoshi, Yasuhiro Fujisawa, Taku Fujimura, Hiroo Hata, Yoshihiro Ishida, Kenji Kabashima

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Abstract

Cancer immunotherapy has highlighted the clinical relevance of enhancing anti-tumor response of CD8+ T cells in several cancer types. Little is known, however, about the involvement of the immune system in extramammary Paget's disease (EMPD). We examined the cytotoxicity and the effector functions of CD8+ T cells using paired samples of peripheral blood and tumors by flow cytometry. Expression levels of perforin, granzyme B, IFN-g, TNF-a, and IL-2 in CD8+ tumor-infiltrating lymphocytes (TILs) were significantly lower than those in CD8+ T cells of peripheral blood. Significantly higher expression of PD-1 was found in CD8+TILs than in CD8+ T cells of peripheral blood. A high number of CD8+ cells was significantly associated with poor overall survival (OS) adjusted with age, sex, and clinical stage (hazard ratio [HR] = 5.03, P = 0.045, 95% confidence interval [CI] 1.03-24.4). On the other hand, the number of PD-1+ cells was not associated with OS or disease-free survival (DFS). Moreover, we found that tumor cells produced immunosuppressive molecule indoleamine 2,3-dyoxygenae (IDO). In conclusion, CD8+ TILs displayed an exhausted phenotype in EMPD. IDO expression seemed more relevant in inducing CD8 exhaustion than PD-1 upregulation or PD-L1 expression by immune cells. Restoring the effector functions of CD8+ TILs could be an effective treatment strategy for advanced EMPD.

Original languageEnglish
Article numbere0211135
JournalPLoS One
Volume14
Issue number1
DOIs
Publication statusPublished - 2019 Jan 1

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Extramammary Paget's Disease
T-cells
Tumor-Infiltrating Lymphocytes
Tumors
T-lymphocytes
Lymphocytes
T-Lymphocytes
neoplasms
Neoplasms
lymphocytes
Blood
Immunosuppressive Agents
blood
Immunotherapy
Disease-Free Survival
Interleukin-2
Immune System
Flow cytometry
Flow Cytometry
Immune system

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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Iga, N., Otsuka, A., Yamamoto, Y., Nakashima, C., Honda, T., Kitoh, A., ... Kabashima, K. (2019). Accumulation of exhausted CD8+ T cells in extramammary Paget's disease. PLoS One, 14(1), [e0211135]. https://doi.org/10.1371/journal.pone.0211135

Accumulation of exhausted CD8+ T cells in extramammary Paget's disease. / Iga, Natsuko; Otsuka, Atsushi; Yamamoto, Yosuke; Nakashima, Chisa; Honda, Tetsuya; Kitoh, Akihiko; Nakajima, Saeko; Egawa, Gyohei; Nomura, Takashi; Dainichi, Teruki; Matsushita, Shigeto; Tanizaki, Hideaki; Yamamoto, Yuki; Funakoshi, Takeru; Fujisawa, Yasuhiro; Fujimura, Taku; Hata, Hiroo; Ishida, Yoshihiro; Kabashima, Kenji.

In: PLoS One, Vol. 14, No. 1, e0211135, 01.01.2019.

Research output: Contribution to journalArticle

Iga, N, Otsuka, A, Yamamoto, Y, Nakashima, C, Honda, T, Kitoh, A, Nakajima, S, Egawa, G, Nomura, T, Dainichi, T, Matsushita, S, Tanizaki, H, Yamamoto, Y, Funakoshi, T, Fujisawa, Y, Fujimura, T, Hata, H, Ishida, Y & Kabashima, K 2019, 'Accumulation of exhausted CD8+ T cells in extramammary Paget's disease', PLoS One, vol. 14, no. 1, e0211135. https://doi.org/10.1371/journal.pone.0211135
Iga N, Otsuka A, Yamamoto Y, Nakashima C, Honda T, Kitoh A et al. Accumulation of exhausted CD8+ T cells in extramammary Paget's disease. PLoS One. 2019 Jan 1;14(1). e0211135. https://doi.org/10.1371/journal.pone.0211135
Iga, Natsuko ; Otsuka, Atsushi ; Yamamoto, Yosuke ; Nakashima, Chisa ; Honda, Tetsuya ; Kitoh, Akihiko ; Nakajima, Saeko ; Egawa, Gyohei ; Nomura, Takashi ; Dainichi, Teruki ; Matsushita, Shigeto ; Tanizaki, Hideaki ; Yamamoto, Yuki ; Funakoshi, Takeru ; Fujisawa, Yasuhiro ; Fujimura, Taku ; Hata, Hiroo ; Ishida, Yoshihiro ; Kabashima, Kenji. / Accumulation of exhausted CD8+ T cells in extramammary Paget's disease. In: PLoS One. 2019 ; Vol. 14, No. 1.
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