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[This article belongs to Volume - 70, Issue - 5]
Published on : 2025-05-21 14:33:25
Article Code: AMJ-21-05-2025-12318
Title : Spatial Transcriptomic Mapping of the Tumor-Immune Microenvironment in Immunotherapy-Resistant Melanoma Reveals Fibroblast-Mediated T-cell Exclusion
Author(s) : Dr. Isabella Rossi, Dr. Michael Chang, Dr. Nadia Hussein
Abstract :
Immune checkpoint inhibitor (ICI) resistance in metastatic melanoma involves complex stromal-immune crosstalk.
Utilizing spatial transcriptomics (10x Genomics Visium) and multiplex ion beam imaging (MIBI) of 120 patient
biopsies, we identified therapy-resistant tumor regions characterized by collagen-dense extracellular matrix
produced by CXCL12-expressing cancer-associated fibroblasts (CAFs). These CAFs established physical barriers
excluding CD8+ T-cells from tumor nests while recruiting regulatory T-cells through CCL22 secretion. Pharmacological
inhibition of lysyl oxidase (LOX) enzymatic activity disrupted collagen crosslinking, restored T-cell infiltration, and
resensitized resistant tumors to anti-PD-1 therapy in humanized mouse models. This work elucidates stromal
determinants of ICI failure.