Mebane Richard H, Noel Teia, Ing Nathan, Gouin Kenneth H, Shah Aagam, Zitser David, Martinez Andrew, Gupta Gaorav, Demaria Sandra, Galluzzi Lorenzo, Ho Alice, McArthur Heather, Shiao Stephen L, Knott Simon R V
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
iScience. 2025 Jun 2;28(7):112808. doi: 10.1016/j.isci.2025.112808. eCollection 2025 Jul 18.
Tertiary lymphoid structures (TLSs) are associated with improved cancer immunotherapy responses. However, TLSs vary in their ability to elicit anticancer immune activity, so it is important to develop databases that allow study of variables that regulate their function. We applied single RNA molecule resolution imaging to longitudinal biopsies taken from women with TLS-enriched triple negative breast cancers prior to therapy, after pembrolizumab and after pembrolizumab plus radiation therapy. We developed a computational framework to align and analyze spatial trajectories between TLSs and tumor beds. Tumors with higher T cell infiltration rates were eradicated after pembrolizumab. In contrast, those with lower malignant cell and T cell interaction rates at baseline showed CXCL9 macrophage infiltration after pembrolizumab, and infiltration of T cells expressing CXCL9-associated programs prior to cancer cell removal after radiation therapy. This manuscript describes single RNA molecule resolution profiling of breast tumors bearing tertiary lymphoid structures throughout an immunotherapy response.
三级淋巴结构（TLSs）与癌症免疫治疗反应的改善相关。然而，TLSs引发抗癌免疫活性的能力各不相同，因此开发能够研究调节其功能的变量的数据库非常重要。我们将单RNA分子分辨率成像应用于从富含TLS的三阴性乳腺癌女性患者治疗前、帕博利珠单抗治疗后以及帕博利珠单抗联合放射治疗后的纵向活检样本。我们开发了一个计算框架来对齐和分析TLSs与肿瘤床之间的空间轨迹。帕博利珠单抗治疗后，T细胞浸润率较高的肿瘤被根除。相比之下，那些在基线时恶性细胞与T细胞相互作用率较低的肿瘤在帕博利珠单抗治疗后显示出CXCL9巨噬细胞浸润，并且在放射治疗后癌细胞清除之前有表达CXCL9相关程序的T细胞浸润。本文描述了在整个免疫治疗反应过程中对带有三级淋巴结构的乳腺肿瘤进行单RNA分子分辨率分析的情况。
