Single-Cell and Spatial Proteo-Transcriptomic Profiling Reveals Immune Infiltration Heterogeneity Associated With Neuroendocrine Features in Small Cell Lung Cancer

Authors

Ying Jin
Yuefeng Wu
Alexandre Reuben
Liang Zhu
Carl M Gay
Qingzhe Wu
Xintong Zhou
Haomin Mo
Qi Zheng
Junyu Ren
Zhaoyuan Fang
Teng Peng
Nan Wang
Liang Ma
Yun Fan
Hai Song
Jianjun Zhang
Ming Chen

Publication Date

9-4-2024

Journal

Cell Discovery

Abstract

Small cell lung cancer (SCLC) is an aggressive pulmonary neuroendocrine malignancy featured by cold tumor immune microenvironment (TIME), limited benefit from immunotherapy, and poor survival. The spatial heterogeneity of TIME significantly associated with anti-tumor immunity has not been systemically studied in SCLC. We performed ultra-high-plex Digital Spatial Profiling on 132 tissue microarray cores from 44 treatment-naive limited-stage SCLC tumors. Incorporating single-cell RNA-sequencing data from a local cohort and published SCLC data, we established a spatial proteo-transcriptomic landscape covering over 18,000 genes and 60 key immuno-oncology proteins that participate in signaling pathways affecting tumorigenesis, immune regulation, and cancer metabolism across 3 pathologically defined spatial compartments (pan-CK-positive tumor nest; CD45/CD3-positive tumor stroma; para-tumor). Our study depicted the spatial transcriptomic and proteomic TIME architecture of SCLC, indicating clear intra-tumor heterogeneity dictated via canonical neuroendocrine subtyping markers; revealed the enrichment of innate immune cells and functionally impaired B cells in tumor nest and suggested potentially important immunoregulatory roles of monocytes/macrophages. We identified RE1 silencing factor (REST) as a potential biomarker for SCLC associated with low neuroendocrine features, more active anti-tumor immunity, and prolonged survival.

Keywords

Cancer microenvironment, Small-cell lung cancer

Comments

Supplementary Materials

Data Availability Statement

PMID: 39231924