Abstract：
Heterogeneous resistance to immunotherapy remains a major challenge in cancer treatment, often leading to disease progression and death. Using CITE-seq and matched 40-plex PhenoCycler tissue imaging, we performed longitudinal multimodal single-cell analysis of tumors from metastatic melanoma patients with innate resistance, acquired resistance, or response to immunotherapy. We established the multimodal integration toolkit to align transcriptomic features, cellular epitopes, and spatial information to provide deeper insights into the tumors. With longitudinal analysis, we identified an \"immune-striving\" tumor microenvironment marked by peri-tumor lymphoid aggregates and low infiltration of T cells in the tumor and the emergence of MITF+SPARCL1+ and CENPF+ melanoma subclones after therapy. The enrichment of B cell-associated signatures in the molecular composition of lymphoid aggregates was associated with better survival. These findings provide further insights into the establishment of microenvironmental cell interactions and molecular composition of spatial structures that could inform therapeutic intervention.
摘要：
对免疫疗法的异质性耐药性仍然是癌症治疗中的主要挑战。经常导致疾病进展和死亡。使用TE-seq和匹配的40-plexPhenoCycler组织成像，我们对具有先天抵抗的转移性黑色素瘤患者的肿瘤进行了纵向多模态单细胞分析，获得性抵抗力，或对免疫疗法的反应。我们建立了多模式整合工具包来对齐转录组特征，细胞表位,和空间信息，以提供更深入的了解肿瘤。通过纵向分析，我们确定了一个“免疫稳定”的肿瘤微环境，其特征是肿瘤周围淋巴样聚集体和肿瘤中T细胞的低浸润，以及治疗后MITFSPARCL1和CENPF黑色素瘤亚克隆的出现。B细胞相关特征在淋巴聚集体的分子组成中的富集与更好的存活相关。这些发现为建立微环境细胞相互作用和空间结构的分子组成提供了进一步的见解，可以为治疗干预提供信息。
