Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: Prognostic outcome and comparison with bladder cancer

Tsukasa Masuda, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Ryohei Takahashi, Tadatsugu Anno, Ryohei Kufukihara, Kazunori Shojo, Shuji Mikami, Toshiaki Shinojima, Kazuhiro Kakimi, Tatsuhiko Tsunoda, Eriko Aimono, Hiroshi Nishihara, Ryuichi Mizuno, Mototsugu Oya

研究成果: Article査読

抄録

Background The aims of this study were (1) to clarify the impact of tertiary lymphoid structure (TLS) status on the outcome and immunogenomic profile of human clear cell renal cell carcinoma (ccRCC) and (2) to determine phenotypic differences in TLSs between different types of genitourinary cancer, that is, urinary ccRCC and bladder cancer. Methods We performed a quantitative immunohistological analysis of ccRCC tissue microarrays and conducted integrated genome mutation analysis by next-generation sequencing and methylation array analysis. Since the tumor immune microenvironment of ccRCC often differs from that of other cancer types, we analyzed the phenotypic differences in TLSs between ccRCC and in-house bladder cancer specimens. Results Varying distribution patterns of TLSs were observed throughout ccRCC tumors, revealing that the presence of TLSs was related to poor prognosis. An analysis of genomic alterations based on TLS status in ccRCC revealed that alterations in the PI3K-mTOR pathway were highly prevalent in TLS-positive tumors. DNA methylation profiling also revealed distinct differences in methylation signatures among ccRCC samples with different TLS statuses. However, the TLS characteristics of ccRCC and bladder cancer markedly differed: TLSs had the exact opposite prognostic impact on bladder cancer as on ccRCC. The maturity and spatial distribution of TLSs were significantly different between the two cancer types; TLSs were more mature with follicle-like germinal center organization and likely to be observed inside the tumor in bladder cancer. Labeling for CD8, FOXP3, PD-1, and PD-L1 showed marked differences in the diversity of the immune microenvironment surrounding TLSs. The proportions of CD8-, FOXP3-, and PD-L1-positive cells were significantly higher in TLSs in bladder cancer than in TLSs in ccRCC; rather the proportion of PD-1-positive cells was significantly higher in TLSs in ccRCC than in TLSs in bladder cancer. Conclusion The immunobiology of ccRCC is unique, and various cancerous phenomena conflict with that seen in other cancer types; therefore, comparing the TLS characteristics between ccRCC and bladder cancer may help reveal differences in the prognostic impact, maturity and spatial distribution of TLSs and in the immune environment surrounding TLSs between the two cancers.

本文言語English
論文番号e003883
ジャーナルJournal for ImmunoTherapy of Cancer
10
3
DOI
出版ステータスPublished - 2022 3月 21

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学
  • 分子医療
  • 腫瘍学
  • 薬理学
  • 癌研究

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