Biomarkers of Pathologic Complete Response to Neoadjuvant Immunotherapy in Mismatch Repair–Deficient Colorectal Cancer

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 · 发表于：Clinical Cancer Research · 年份：2023 · DOI：10.1158/1078-0432.ccr-23-2213 · 被引用次数：33 · 研究领域：Cancer Immunotherapy and Biomarkers、Genetic factors in colorectal cancer、Ferroptosis and cancer prognosis

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...