@article{e56fb9ad0cb14b90bd0b508488ef6325,
title = "Intratumoral adaptive immunosuppression and type 17 immunity in mismatch repair proficient colorectal tumors",
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.",
author = "Llosa, {Nicolas J.} and Brandon Luber and Tam, {Ada J.} and Smith, {Kellie N.} and Nicholas Siegel and Awan, {Anas H.} and Hongni Fan and Teniola Oke and Jiajia Zhang and Jada Domingue and Engle, {Elizabeth L.} and Roberts, {Charles A.} and Bartlett, {Bjarne R.} and Aulakh, {Laveet K.} and Thompson, {Elizabeth D.} and Taube, {Janis M.} and Durham, {Jennifer N.} and Sears, {Cynthia L.} and Le, {Dung T.} and Diaz, {Luis A.} and Pardoll, {Drew M.} and Hao Wang and Anders, {Robert A.} and Franck Housseau",
note = "Funding Information: N.J. Llosa reports receiving other commercial research support from and is a consultant/advisory board member for Bristol-Myers Squibb. K.N. Smith reports receiving speakers bureau honoraria from Neon Therapeutics. J.M. Taube reports receiving commercial research grants from Bristol-Myers Squibb, and is a consultant/advisory board member for Bristol-Myers Squibb, Merck, Amgen, and AstraZeneca. C.L. Sears reports receiving commercial research grants from Bristol-Myers Squibb, and is a consultant/ advisory board member for Merck. D.T. Le reports receiving commercial research grants from Bristol-Myers Squibb and Merck, speakers bureau honoraria from Merck, and is a consultant/advisory board member for Bristol-Myers Squibb. L.A. Diaz is an employee of Jounce Therapeutics and Personal Genome Diagnostics (PGDx), reports receiving commercial research grants from Merck, holds ownership interest (including patents) in Personal Genome Diagnostics (PGDx), PapGene, Jounce Therapeutics, and NeoPhore, and is a consultant/advisory board member for Merck, Personal Genome Diagnostics (PGDx), and Neophore. D.M. Pardoll reports receiving commercial research grants from AstraZeneca, Bristol-Myers Squibb, Compugen, Ervaxx, and Potenza, holds ownership interest (including patents) in Aduro Biotech, DNAtrix, Potenza, Tizona, Trieza, WindMil, and Dracen, and is a consultant/advisory board member for Rock Springs, Merck, Janssen, Immunomic, FLX Bio, Five Prime, Dynavax, Camden Partners, Bayer, and Amgen. R.A. Anders reports receiving speakers bureau honoraria from Bristol-Myers Squibb, Merck, and AstraZeneca. F. Housseau reports receiving commercial research grants from Bristol-Myers Squibb. No potential conflicts of interest were disclosed by the other authors. Funding Information: All the authors are supported by the Bloomberg~Kimmel Institute for Cancer Immunotherapy, Bloomberg Philanthropies, and NIH grants P30 DK089502 and P30 CA006973. This work is also supported by The Swim Across America foundation (to F. Housseau and L.A. Diaz), The Mark Foundation for Cancer Research (to K.N. Smith, J. Zhang, and D.M. Pardoll), the Commonwealth Foundation (to F. Housseau and C.L. Sears), a Cancer Research Institute/ FightColorectalCancer I/O grant (to F. Housseau and C.L. Sears), NIH grants R01 CA203891 (to F. Housseau) and R01 CA142779 (to J.M. Taube and D.M. Pardoll). This work is also supported by NIH Gastrointestinal Specialized Programs of Research Excellence (SPORE) grant (P50 CA062924, to F. Hous-seau), T32 CA193145, Merck, Bristol Myers Squibb, the Stand Up to Cancer Immunology Dream Team Translational Research Grant (SU2C-AACR-DT1012), and the Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17). Stand Up to Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Publisher Copyright: {\textcopyright} 2019 American Association for Cancer Research Inc.. All rights reserved.",
year = "2019",
month = sep,
day = "1",
doi = "10.1158/1078-0432.CCR-19-0114",
language = "English (US)",
volume = "25",
pages = "5250--5259",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",
}