Spatiotemporal single-cell analysis decodes cellular dynamics underlying different responses to immunotherapy in colorectal cancer

• DOI: 10.1016/j.ccell.2024.06.009
• Publication Date: 2024-07-08T14:50:24Z
• Authors: Yuqing Chen; Dongfang Wang; Yingjie Li; Lu Qi; Wen Si; Yufei Bo; Xueyan Chen; Zhaochen Ye; Hongtao Fan; Baolin Liu; Chang Liu; Li Zhang; Xiaoyan Zhang; Zhongwu Li; Linna Zhu; Aiwen Wu; Zemin Zhang
• Keywords: Male; Lymphocytes, Tumor-Infiltrating; Programmed Cell Death 1 Receptor; Humans; Female; Immunotherapy; Single-Cell Analysis; CD8-Positive T-Lymphocytes; Colorectal Neoplasms; Immune Checkpoint Inhibitors

Expanding the efficacy of immune checkpoint blockade (ICB) in colorectal cancer (CRC) presses for a comprehensive understanding of treatment responsiveness. Here, we analyze multiple sequential single-cell samples from 22 patients undergoing PD-1 blockade to map the evolution of local and systemic immunity of CRC patients. In tumors, we identify coordinated cellular programs exhibiting distinct response associations. Specifically, exhausted T (Tex) or tumor-reactive-like CD8+ T (Ttr-like) cells are closely related to treatment efficacy, and Tex cells show correlated proportion changes with multiple other tumor-enriched cell types following PD-1 blockade. In addition, we reveal the less-exhausted phenotype of blood-associated Ttr-like cells in tumors and find that their higher abundance suggests better treatment outcomes. Finally, a higher major histocompatibility complex (MHC) II-related signature in circulating CD8+ T cells at baseline is linked to superior responses. Our study provides insights into the spatiotemporal cellular dynamics following neoadjuvant PD-1 blockade in CRC.