TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

Tsuyoshi Hamada, Thing Rinda Soong, Yohei Masugi, Keisuke Kosumi, Jonathan A. Nowak, Annacarolina da Silva, Xinmeng Jasmine Mu, Tyler S. Twombly, Hideo Koh, Juhong Yang, Mingyang Song, Li Liu, Mancang Gu, Yan Shi, Katsuhiko Nosho, Teppei Morikawa, Kentaro Inamura, Sachet A. Shukla, Catherine J. Wu, Levi A. GarrawayXuehong Zhang, Kana Wu, Jeffrey A. Meyerhardt, Andrew T. Chan, Jonathan N. Glickman, Scott J. Rodig, Gordon J. Freeman, Charles S. Fuchs, Reiko Nishihara, Marios Giannakis, Shuji Ogino

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Inhibitors targeting the PDCD1 (programmed cell death 1, PD-1) immune checkpoint pathway have revolutionized cancer treatment strategies. The TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PDCD1 ligand 1, PD-L1) expression and tumor-infiltrating lymphocytes (TIL) has been proposed to predict response to immunotherapy. It remains to be determined clinical, pathological, and molecular features of TIME subtypes of colorectal cancer. Using 812 colon and rectal carcinoma cases from the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association of tumor characteristics and survival outcomes with four TIME subtypes (TIME 1, CD274low/TILabsent; TIME 2, CD274high/TILpresent; TIME 3, CD274low/TILpresent; and TIME 4, CD274high/TILabsent). In survival analyses, Cox proportional hazards models were adjusted for potential confounders, including microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP) status, LINE-1 methylation level, and KRAS, BRAF, and PIK3CA mutation status. TIME subtypes 1, 2, 3 and 4 had 218 (27%), 117 (14%), 103 (13%), and 374 (46%) colorectal cancer cases, respectively. Compared with TIL-absent subtypes (TIME 1 and 4), TIL-present subtypes (TIME 2 and 3) were associated with high-level MSI, high-degree CIMP, BRAF mutation, and higher amounts of neoantigens (p < 0.001). TIME subtypes were not significantly associated with colorectal cancer-specific or overall survival. In conclusion, TIL-present TIME subtypes of colorectal cancer are associated with high levels of MSI and neoantigen load, supporting better responsiveness to cancer immunotherapy. Further studies examining tumor molecular alterations and additional factors in the tumor microenvironment may inform development of immunoprevention and immunotherapy strategies.

Original languageEnglish
Article numbere1442999
JournalOncoImmunology
Volume7
Issue number7
DOIs
Publication statusPublished - 2018 Jul 3
Externally publishedYes

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Keywords

  • Adaptive immunity
  • biomarkers
  • cohort studies
  • colorectal neoplasms
  • immunology
  • immunotherapy
  • molecular pathological epidemiology
  • survival analysis
  • T-lymphocytes
  • tumor microenvironment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Hamada, T., Soong, T. R., Masugi, Y., Kosumi, K., Nowak, J. A., da Silva, A., Mu, X. J., Twombly, T. S., Koh, H., Yang, J., Song, M., Liu, L., Gu, M., Shi, Y., Nosho, K., Morikawa, T., Inamura, K., Shukla, S. A., Wu, C. J., ... Ogino, S. (2018). TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. OncoImmunology, 7(7), [e1442999]. https://doi.org/10.1080/2162402X.2018.1442999