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. Garraway & 11 others Xuehong 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

8 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

Fingerprint

Tumor-Infiltrating Lymphocytes
Colorectal Neoplasms
Immunity
Ligands
Neoplasms
Microsatellite Instability
Immunotherapy
CpG Islands
Tumor Microenvironment
CD274 Antigen
Cell Death
Phenotype
Mutation
Health

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

TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. / Hamada, Tsuyoshi; Soong, Thing Rinda; Masugi, Yohei; Kosumi, Keisuke; Nowak, Jonathan A.; da Silva, Annacarolina; Mu, Xinmeng Jasmine; Twombly, Tyler S.; Koh, Hideo; Yang, Juhong; Song, Mingyang; Liu, Li; Gu, Mancang; Shi, Yan; Nosho, Katsuhiko; Morikawa, Teppei; Inamura, Kentaro; Shukla, Sachet A.; Wu, Catherine J.; Garraway, Levi A.; Zhang, Xuehong; Wu, Kana; Meyerhardt, Jeffrey A.; Chan, Andrew T.; Glickman, Jonathan N.; Rodig, Scott J.; Freeman, Gordon J.; Fuchs, Charles S.; Nishihara, Reiko; Giannakis, Marios; Ogino, Shuji.

In: OncoImmunology, Vol. 7, No. 7, e1442999, 03.07.2018.

Research output: Contribution to journalArticle

Hamada, T, Soong, TR, Masugi, Y, Kosumi, K, Nowak, JA, da Silva, A, Mu, XJ, Twombly, TS, Koh, H, Yang, J, Song, M, Liu, L, Gu, M, Shi, Y, Nosho, K, Morikawa, T, Inamura, K, Shukla, SA, Wu, CJ, Garraway, LA, Zhang, X, Wu, K, Meyerhardt, JA, Chan, AT, Glickman, JN, Rodig, SJ, Freeman, GJ, Fuchs, CS, Nishihara, R, Giannakis, M & 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, vol. 7, no. 7, e1442999. https://doi.org/10.1080/2162402X.2018.1442999
Hamada, Tsuyoshi ; Soong, Thing Rinda ; Masugi, Yohei ; Kosumi, Keisuke ; Nowak, Jonathan A. ; da Silva, Annacarolina ; Mu, Xinmeng Jasmine ; Twombly, Tyler S. ; Koh, Hideo ; Yang, Juhong ; Song, Mingyang ; Liu, Li ; Gu, Mancang ; Shi, Yan ; Nosho, Katsuhiko ; Morikawa, Teppei ; Inamura, Kentaro ; Shukla, Sachet A. ; Wu, Catherine J. ; Garraway, Levi A. ; Zhang, Xuehong ; Wu, Kana ; Meyerhardt, Jeffrey A. ; Chan, Andrew T. ; Glickman, Jonathan N. ; Rodig, Scott J. ; Freeman, Gordon J. ; Fuchs, Charles S. ; Nishihara, Reiko ; Giannakis, Marios ; Ogino, Shuji. / TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas. In: OncoImmunology. 2018 ; Vol. 7, No. 7.
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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.",
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T1 - TIME (Tumor Immunity in the MicroEnvironment) classification based on tumor CD274 (PD-L1) expression status and tumor-infiltrating lymphocytes in colorectal carcinomas

AU - Hamada, Tsuyoshi

AU - Soong, Thing Rinda

AU - Masugi, Yohei

AU - Kosumi, Keisuke

AU - Nowak, Jonathan A.

AU - da Silva, Annacarolina

AU - Mu, Xinmeng Jasmine

AU - Twombly, Tyler S.

AU - Koh, Hideo

AU - Yang, Juhong

AU - Song, Mingyang

AU - Liu, Li

AU - Gu, Mancang

AU - Shi, Yan

AU - Nosho, Katsuhiko

AU - Morikawa, Teppei

AU - Inamura, Kentaro

AU - Shukla, Sachet A.

AU - Wu, Catherine J.

AU - Garraway, Levi A.

AU - Zhang, Xuehong

AU - Wu, Kana

AU - Meyerhardt, Jeffrey A.

AU - Chan, Andrew T.

AU - Glickman, Jonathan N.

AU - Rodig, Scott J.

AU - Freeman, Gordon J.

AU - Fuchs, Charles S.

AU - Nishihara, Reiko

AU - Giannakis, Marios

AU - Ogino, Shuji

PY - 2018/7/3

Y1 - 2018/7/3

N2 - 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.

AB - 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.

KW - Adaptive immunity

KW - biomarkers

KW - cohort studies

KW - colorectal neoplasms

KW - immunology

KW - immunotherapy

KW - molecular pathological epidemiology

KW - survival analysis

KW - T-lymphocytes

KW - tumor microenvironment

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DO - 10.1080/2162402X.2018.1442999

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