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 language | English (US) |
|---|---|
| Pages (from-to) | 5250-5259 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 25 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2019 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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 journal › Article
}
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=85071785117&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071785117&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0114
DO - 10.1158/1078-0432.CCR-19-0114
M3 - Article
C2 - 31061070
AN - SCOPUS:85071785117
VL - 25
SP - 5250
EP - 5259
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 17
ER -