近日，英国剑桥大学H. Raza Ali等研究人员合作揭示三阴性乳腺癌免疫疗法反应的空间预测因素。相关论文于2023年9月6日在线发表在《自然》杂志上。

由于免疫检查点阻断疗法（ICB）针对的是细胞-细胞间的相互作用，因此研究人员揭示了多细胞空间组织对反应的影响，并探讨了ICB如何重塑肿瘤微环境。研究表明，细胞表型、活化状态和空间位置密切相关，影响着ICB的效果，并且在治疗早期敏感肿瘤和耐药肿瘤中存在差异。研究人员使用成像质谱分析了新辅助ICB随机试验患者肿瘤中43种蛋白质的原位表达，在三个时间点取样（基线，n=243；治疗早期，n=207；治疗后，n=210）。

多变量模型显示，增殖的CD8⁺TCF1⁺ T细胞和MHCII⁺癌细胞的比例是预测反应的主要因素，其次是癌症与B细胞和颗粒酶B⁺ T细胞的免疫相互作用。在治疗过程中，有反应的肿瘤含有大量颗粒酶B⁺ T细胞，而有反应的肿瘤则以CD15⁺癌细胞为特征。结合治疗前和治疗时的组织特征可以最好地预测反应，这表明早期活检在指导适应性治疗中的作用。这些研究结果表明，多细胞空间组织是ICB效果的主要决定因素，并表明在原位系统地枚举多细胞空间组织有助于实现精准免疫肿瘤学。

据悉，ICB能使一些三阴性乳腺癌患者获益，但如何区分有反应者和无反应者尚不清楚。

附：英文原文

Title: Spatial predictors of immunotherapy response in triple-negative breast cancer

Author: Wang, Xiao Qian, Danenberg, Esther, Huang, Chiun-Sheng, Egle, Daniel, Callari, Maurizio, Bermejo, Begoa, Dugo, Matteo, Zamagni, Claudio, Thill, Marc, Anton, Anton, Zambelli, Stefania, Russo, Stefania, Ciruelos, Eva Maria, Greil, Richard, Gyrffy, Balzs, Semiglazov, Vladimir, Colleoni, Marco, Kelly, Catherine M., Mariani, Gabriella, Del Mastro, Lucia, Biasi, Olivia, Seitz, Robert S., Valagussa, Pinuccia, Viale, Giuseppe, Gianni, Luca, Bianchini, Giampaolo, Ali, H. Raza

Issue&Volume: 2023-09-06

Abstract: Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell–cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer–immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology. Imaging mass cytometry is used to map the multicellular dynamics of immune checkpoint blockade-treated triple-negative breast cancer, finding that key proliferative fractions and cell–cell interactions drive response, and immunotherapy distinctively remodels tumour structure.

DOI: 10.1038/s41586-023-06498-3

Source: https://www.nature.com/articles/s41586-023-06498-3