创作:szx 审核:szx 2019年09月09日
  • 纳入19名转移性结直肠癌患者,其中13名对PD-1单抗治疗应答,6名不应答,对比原发结肠肿瘤组织中44个免疫相关基因的表达;
  • 鉴定出10个基因的表达与患者对PD-1单抗治疗的应答相关,这些基因的组合可以0.67的敏感性及0.92的特异性区分应答患者与不应答患者;
  • 应答患者的CD4、CD8A、LAG3、MMP9、CD274及IDO1的表达上调,而RORC、VEGFA、ICOSLG及IL-23R的表达下调;
  • 应答患者的T细胞浸润、免疫检查点基因表达增加,Th17相关基因表达降低。
约10%的错配修复正常的结直肠癌患者可对PD-1单抗治疗产生应答。Clinical Cancer Research上发表的一项最新研究,对别了错配修复正常的转移性结直肠癌患者的原发肿瘤组织中的基因表达差异,鉴定出10个与PD-1单抗治疗应答相关的基因,发现IL-17信号可能抑制了患者对免疫检查点抑制剂治疗的应答,提示靶向IL-17信号通路或可与免疫检查点抑制剂联用以治疗结直肠癌。

Intratumoral Adaptive Immunosuppression and Type 17 Immunity in Mismatch Repair Proficient Colorectal Tumors



2019-05-06, Article

Abstract & Authors:展开

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.

First Authors:
Nicolas J Llosa

Correspondence Authors:
Robert A Anders,Franck Housseau

All Authors:
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 Diaz,Drew M Pardoll,Hao Wang,Robert A Anders,Franck Housseau