小柯机器人

2021年5月6日，比利时鲁汶大学Diether Lambrechts等研究人员合作在《自然—医学》杂志在线发表论文，绘制出抗PD1治疗乳腺癌患者期间肿瘤内变化的单细胞图谱。

为了理解为什么只有一部分肿瘤对免疫检查点阻断（ICB）产生反应，研究人员对荷尔蒙受体阳性或三阴性乳腺癌的患者在手术前进行了抗PD1治疗。对接受过抗PD1治疗的初治患者或未接受过PD1治疗前接受新辅助化疗的患者进行配对的治疗前和治疗时活检（n=11），并对它们进行单细胞转录组、T细胞受体和蛋白质组分析。三分之一的肿瘤包含表达PD1的T细胞，无论抗癌亚型如何，抗PD1治疗均可使其克隆扩增。扩增主要涉及CD8⁺T细胞，其具有明显的细胞毒活性（PRF1、GZMB）、免疫细胞归巢（CXCL13）和耗竭标记（HAVCR2、LAG3），以及以T-helper-1（IFNG）为特征的CD4⁺T细胞）和卵泡辅助细胞（BCL6、CXCR5）标记。

在治疗前活检中，免疫调节性树突状细胞（PD-L1⁺）、特定巨噬细胞表型（CCR2⁺或MMP9⁺）和具有主要组织相容性复合物I/II类表达癌细胞的相对频率与T细胞扩增呈正相关。相反，未分化的前效应子/记忆T细胞（TCF7⁺、GZMK⁺）或抑制性巨噬细胞（CX3CR1⁺、C3⁺）与T细胞扩增呈负相关。总体而言，这些数据确定了抗PD1治疗后与T细胞扩增呈正相关或负相关的各种免疫表型和相关基因集，并阐明了乳腺癌中抗PD1治疗反应的异质性。

据了解，ICB结合新辅助化疗可改善乳腺癌的病理完全缓解。

附：英文原文

Title: A single-cell map of intratumoral changes during anti-PD1 treatment of patients with breast cancer

Author: Ayse Bassez, Hanne Vos, Laurien Van Dyck, Giuseppe Floris, Ingrid Arijs, Christine Desmedt, Bram Boeckx, Marlies Vanden Bempt, Ines Nevelsteen, Kathleen Lambein, Kevin Punie, Patrick Neven, Abhishek D. Garg, Hans Wildiers, Junbin Qian, Ann Smeets, Diether Lambrechts

Issue&Volume: 2021-05-06

Abstract: Immune-checkpoint blockade (ICB) combined with neoadjuvant chemotherapy improves pathological complete response in breast cancer. To understand why only a subset of tumors respond to ICB, patients with hormone receptor-positive or triple-negative breast cancer were treated with anti-PD1 before surgery. Paired pre- versus on-treatment biopsies from treatment-naive patients receiving anti-PD1 (n=29) or patients receiving neoadjuvant chemotherapy before anti-PD1 (n=11) were subjected to single-cell transcriptome, T cell receptor and proteome profiling. One-third of tumors contained PD1-expressing T cells, which clonally expanded upon anti-PD1 treatment, irrespective of tumor subtype. Expansion mainly involved CD8+ T cells with pronounced expression of cytotoxic-activity (PRF1, GZMB), immune-cell homing (CXCL13) and exhaustion markers (HAVCR2, LAG3), and CD4+ T cells characterized by expression of T-helper-1 (IFNG) and follicular-helper (BCL6, CXCR5) markers. In pre-treatment biopsies, the relative frequency of immunoregulatory dendritic cells (PD-L1+), specific macrophage phenotypes (CCR2+ or MMP9+) and cancer cells exhibiting major histocompatibility complex class I/II expression correlated positively with T cell expansion. Conversely, undifferentiated pre-effector/memory T cells (TCF7+, GZMK+) or inhibitory macrophages (CX3CR1+, C3+) were inversely correlated with T cell expansion. Collectively, our data identify various immunophenotypes and associated gene sets that are positively or negatively correlated with T cell expansion following anti-PD1 treatment. We shed light on the heterogeneity in treatment response to anti-PD1 in breast cancer.

DOI: 10.1038/s41591-021-01323-8

Source: https://www.nature.com/articles/s41591-021-01323-8

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
官方网址：https://www.nature.com/nm/
投稿链接：https://mts-nmed.nature.com/cgi-bin/main.plex