Journal for immunotherapy of cancer
Extracellular matrix collagen remodeling predicts resistance to immune checkpoint blockade in mismatch repair-deficient endometrial cancer
By Grau Bejar JF, Zeng Q, Abdelsayed V and 13 others.
Abstract
Background
Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic paradigm for mismatch repair-deficient endometrial cancer (MMRd EC). However, a considerable subset of patients fails to achieve durable clinical benefit. This pronounced interpatient variability underscores the urgent unmet need for mechanistic predictive biomarkers beyond MMRd status alone to guide clinical decision-making.
Methods
We performed a multiproteomic mass spectrometry analysis on tumor specimens from an advanced or recurrent MMRd EC cohort stratified into ICI responders (ICI-R) and non-responders (ICI-NR). Proteomic signatures were validated spatially and structurally using whole-section Masson’s Trichrome digital imaging and polarization-resolved second-harmonic generation microscopy. Machine learning algorithms were constructed to integrate extracellular matrix (ECM) structural metrics with immune parameters to build a multiparametric predictive model of ICI resistance.