结直肠癌
微卫星不稳定性
CD8型
免疫疗法
免疫系统
免疫检查点
癌症研究
肿瘤微环境
癌症
生物
新辅助治疗
人类白细胞抗原
T细胞
医学
免疫学
抗原
内科学
基因
乳腺癌
等位基因
生物化学
微卫星
作者
Jianxia Li,Huabin Hu,Ge Qin,Fan Bai,Xianrui Wu,Haoxian Ke,Jianwei Zhang,Yuqian Xie,Zehua Wu,Yang Fu,Hongbo Zheng,Longlong Gong,Zhi Xie,Yanhong Deng
标识
DOI:10.1158/1078-0432.ccr-23-2213
摘要
Abstract Purpose: Immune checkpoint inhibitors (ICI) have become the standard of care for patients with mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colorectal cancer. However, biomarkers of response to ICI are still lacking. Experimental Design: Forty-two patients with dMMR colorectal cancer treated with neoadjuvant PD-1 blockade were prospectively enrolled. To identify biomarkers of pathologic complete response (pCR) to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles based on next-generation sequencing, and immune cell density based on multiplex immunofluorescence (mIF) staining. An integrated analysis of single-cell RNA sequencing from our previous study and GSE178341, as well as mIF was performed to further explore the significance of the tumor microenvironment (TME) on pCR response. Results: The tumor mutation burden of both tumor tissue and plasma blood samples was comparable between the pCR and non-pCR groups, while HLA-DQA1 and HLA-DQB1 were significantly overexpressed in the pCR group. Gene signature enrichment analysis showed that pathways including T-cell receptor pathway, antigen presentation pathway were significantly enriched in the pCR group. In addition, higher pre-existing CD8+ T-cell density was associated with pCR response (767.47 per.mm2 vs. 326.64 per.mm2, P = 0.013 Wilcoxon test). Further integrated analysis showed that CD8+ T cells with low PD-1 expression (PD-1lo CD8+ T cells) expressing high levels of TRGC2, CD160, and KLRB1 and low levels of proliferated and exhausted genes were significantly associated with pCR response. Conclusions: Immune-associated transcriptomic features, particularly CD8+ T cells were associated with pCR response to ICI in dMMR colorectal cancer. Heterogeneity of TME within dMMR colorectal cancer may help to discriminate patients with complete response to neoadjuvant ICI.
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