Understanding primary tumor features predicting post-recurrence immunotherapy response in resectable stage III non-small cell lung cancer (NSCLC) could guide adjuvant strategies. We hypothesized that spatial profiling of surgical specimens would reveal microenvironmental determinants of programmed death ligand-1 (PD-L1)-discordant responses to subsequent immunotherapy.
Surgical specimens from eight stage III NSCLC patients with post-recurrence progression were analyzed by Xenium 5K spatial transcriptomics. Patients were stratified into four PD-L1-high (≥50%) non-responders and four PD-L1-negative (< 50%) responders based on primary tumor PD-L1 expression and post-recurrence immune checkpoint inhibitor (ICI) response. Analyses included pathway enrichment, T cell exhaustion mapping, fibroblast subtyping, spatial neighborhoods, and NicheNet inference.
Non-responders displayed elevated glycolysis and hypoxia pathways indicating metabolic reprogramming, while responders did not. Spatial analysis revealed T cell exhaustion proximal to tumors in non-responders with marked attenuation in responders. Fibroblast subtyping identified metabolically active CAFs (meCAFs) enriched adjacent to glycolytic tumors in non-responders, with tighter tumor-meCAF spatial coupling. NicheNet identified meCAF-derived VEGFA as a key signaling mediator targeting tumor cells, with predicted targets including ACKR3, PTGS2, and PLAU, implicating angiogenic-metabolic crosstalk driving immune exclusion.
Spatial profiling reveals that PD-L1-discordant ICI responses are determined by coordinated interactions of metabolically reprogrammed tumors, localized T cell exhaustion, and meCAF-driven signaling. These findings establish meCAF-VEGFA-tumor crosstalk as a therapeutic vulnerability and support spatially-resolved tumor-stroma profiling as a prognostic tool beyond PD-L1 for predicting ICI responses.
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Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Yongjae Kim, Seong-Eun Kim, Bokyung Ann et al.· Journal of Immunology· 0 citations
Colitis-associated colorectal cancer (C-CRC) develops in chronic inflammatory settings, where tumor—microenvironment interactions critically influence progression. Spatial transcriptomics enables analysis of these interactions while preserving tissue architecture. We aimed to define tumor cell states and associated microenvironmental features in C-CRC.
Seven tissue samples from three C-CRC patients were analyzed using consecutive sections processed by 10x Xenium and 10x Visium. Single-cell spatial coordinates from Xenium were integrated with Visium spots for combined spatial transcriptomic analysis.
Xenium profiling identified 3,506,705 cells comprising epithelial, fibroblast, and immune populations. Tumor subclustering revealed two states: proliferating tumor cells enriched for cell-cycle genes (MKI67, TOP2A) and invasive tumor cells with elevated epithelial mesenchymal transition (EMT)-associated genes (CD44, CXCL1). Spatial neighborhood analysis identified a niche unique to invasive tumor cells characterized by proximity to cancer-associated fibroblasts (CAF) and SPP1+ macrophages. Invasive regions showed enrichment of angiogenesis, hypoxia, and inflammatory pathways. Receptor—ligand analysis identified SPP1—CD44 signaling between SPP1+ macrophages and invasive tumor cells. A gene signature distinguishing invasive and proliferating tumor cells stratified TCGA sporadic colorectal cancer samples into invasive-like and proliferating-like groups, with invasive-like tumors enriched for consensus molecular subtype 4.
This integrated spatial transcriptomics study identifies two tumor populations in C-CRC with distinct microenvironmental contexts. The invasive tumor phenotype is associated with CAF and SPP1+ macrophage proximity and SPP1—CD44-mediated signaling, highlighting the tumor microenvironment as a potential therapeutic target in C-CRC.
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Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
Yoonho Lee, Yongjae Kim, J. Baek et al.· Journal of Immunology· 0 citations
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