Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors

Nicolas J. Llosa, Brandon Luber, Ada J. Tam, Kellie N. Smith, Nicholas Siegel, Anas H. Awan, Hongni Fan, Teniola Oke, Jiajia Zhang, Jada Domingue, Elizabeth L. Engle, Charles A. Roberts, Bjarne R. Bartlett, Laveet K. Aulakh, Elizabeth D. Thompson, Janis M. Taube, Jennifer N. Durham, Cynthia L. Sears, Dung T. Le, Luis A. DiazDrew M. Pardoll, Hao Wang, Robert A. Anders, Franck Housseau

Research output: Contribution to journalArticle

Abstract

Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti- PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. Results: Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/ IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. Conclusions: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)5250-5259
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number17
DOIs
StatePublished - Sep 1 2019

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DNA Mismatch Repair
Immunosuppression
Colorectal Neoplasms
Immunity
Immunotherapy
Colon
Tumor Microenvironment
Neoplasms
T-Lymphocytes
Tumor-Infiltrating Lymphocytes
Drug Delivery Systems
Genes
Research Design
Biomarkers
Phenotype
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors. / Llosa, Nicolas J.; Luber, Brandon; Tam, Ada J.; Smith, Kellie N.; Siegel, Nicholas; Awan, Anas H.; Fan, Hongni; Oke, Teniola; Zhang, Jiajia; Domingue, Jada; Engle, Elizabeth L.; Roberts, Charles A.; Bartlett, Bjarne R.; Aulakh, Laveet K.; Thompson, Elizabeth D.; Taube, Janis M.; Durham, Jennifer N.; Sears, Cynthia L.; Le, Dung T.; Diaz, Luis A.; Pardoll, Drew M.; Wang, Hao; Anders, Robert A.; Housseau, Franck.

In: Clinical Cancer Research, Vol. 25, No. 17, 01.09.2019, p. 5250-5259.

Research output: Contribution to journalArticle

Llosa, NJ, Luber, B, Tam, AJ, Smith, KN, Siegel, N, Awan, AH, Fan, H, Oke, T, Zhang, J, Domingue, J, Engle, EL, Roberts, CA, Bartlett, BR, Aulakh, LK, Thompson, ED, Taube, JM, Durham, JN, Sears, CL, Le, DT, Diaz, LA, Pardoll, DM, Wang, H, Anders, RA & Housseau, F 2019, 'Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors', Clinical Cancer Research, vol. 25, no. 17, pp. 5250-5259. https://doi.org/10.1158/1078-0432.CCR-19-0114
Llosa, Nicolas J. ; Luber, Brandon ; Tam, Ada J. ; Smith, Kellie N. ; Siegel, Nicholas ; Awan, Anas H. ; Fan, Hongni ; Oke, Teniola ; Zhang, Jiajia ; Domingue, Jada ; Engle, Elizabeth L. ; Roberts, Charles A. ; Bartlett, Bjarne R. ; Aulakh, Laveet K. ; Thompson, Elizabeth D. ; Taube, Janis M. ; Durham, Jennifer N. ; Sears, Cynthia L. ; Le, Dung T. ; Diaz, Luis A. ; Pardoll, Drew M. ; Wang, Hao ; Anders, Robert A. ; Housseau, Franck. / Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 17. pp. 5250-5259.
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abstract = "Purpose: Approximately 10{\%} of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti- PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. Results: Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/ IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. Conclusions: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.",
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T1 - Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors

AU - Llosa, Nicolas J.

AU - Luber, Brandon

AU - Tam, Ada J.

AU - Smith, Kellie N.

AU - Siegel, Nicholas

AU - Awan, Anas H.

AU - Fan, Hongni

AU - Oke, Teniola

AU - Zhang, Jiajia

AU - Domingue, Jada

AU - Engle, Elizabeth L.

AU - Roberts, Charles A.

AU - Bartlett, Bjarne R.

AU - Aulakh, Laveet K.

AU - Thompson, Elizabeth D.

AU - Taube, Janis M.

AU - Durham, Jennifer N.

AU - Sears, Cynthia L.

AU - Le, Dung T.

AU - Diaz, Luis A.

AU - Pardoll, Drew M.

AU - Wang, Hao

AU - Anders, Robert A.

AU - Housseau, Franck

PY - 2019/9/1

Y1 - 2019/9/1

N2 - Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti- PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. Results: Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/ IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. Conclusions: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.

AB - Purpose: Approximately 10% of patients with mismatch repair-proficient (MMRp) colorectal cancer showed clinical benefit to anti-PD-1 monotherapy (NCT01876511). We sought to identify biomarkers that delineate patients with immunoreactive colorectal cancer and to explore new combinatorial immunotherapy strategies that can impact MMRp colorectal cancer. Experimental Design: We compared the expression of 44 selected immune-related genes in the primary colon tumor of 19 patients with metastatic colorectal cancer (mCRC) who responded (n = 13) versus those who did not (n = 6) to anti- PD-1 therapy (NCT01876511). We define a 10 gene-based immune signature that could distinguish responder from nonresponder. Resected colon specimens (n = 14) were used to validate the association of the predicted status (responder and nonresponder) with the immune-related gene expression, the phenotype, and the function of tumor-infiltrating lymphocytes freshly isolated from the same tumors. Results: Although both IL17Low and IL17High immunoreactive MMRp colorectal cancers are associated with intratumor correlates of adaptive immunosuppression (CD8/ IFNγ and PD-L1/IDO1 colocalization), only IL17Low MMRp tumors (3/14) have a tumor immune microenvironment (TiME) that resembles the TiME in primary colon tumors of patients with mCRC responsive to anti-PD-1 treatment. Conclusions: The detection of a preexisting antitumor immune response in MMRp colorectal cancer (immunoreactive MMRp colorectal cancer) is not sufficient to predict a clinical benefit to T-cell checkpoint inhibitors. Intratumoral IL17-mediated signaling may preclude responses to immunotherapy. Drugs targeting the IL17 signaling pathway are available in clinic, and their combination with T-cell checkpoint inhibitors could improve colorectal cancer immunotherapy.

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