TY - JOUR
T1 - Accumulation of exhausted CD8+ T cells in extramammary Paget's disease
AU - Iga, Natsuko
AU - Otsuka, Atsushi
AU - Yamamoto, Yosuke
AU - Nakashima, Chisa
AU - Honda, Tetsuya
AU - Kitoh, Akihiko
AU - Nakajima, Saeko
AU - Egawa, Gyohei
AU - Nomura, Takashi
AU - Dainichi, Teruki
AU - Matsushita, Shigeto
AU - Tanizaki, Hideaki
AU - Yamamoto, Yuki
AU - Funakoshi, Takeru
AU - Fujisawa, Yasuhiro
AU - Fujimura, Taku
AU - Hata, Hiroo
AU - Ishida, Yoshihiro
AU - Kabashima, Kenji
N1 - Publisher Copyright:
Copyright: © 2019 Iga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0211135
DO - 10.1371/journal.pone.0211135
M3 - Article
C2 - 30682105
AN - SCOPUS:85060542534
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 1
M1 - e0211135
ER -
