Data from Immune Marker Spatial Distribution and Clinical Outcome after PD-1 Blockade in Mismatch Repair–deficient, Advanced Colorectal Carcinomas

Abstract

<div>AbstractPurpose:<p>Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) interaction has led to durable responses in fewer than half of patients with mismatch repair–deficient (MMR-d) advanced colorectal cancers. Immune contexture, including spatial distribution of immune cells in the tumor microenvironment (TME), may predict immunotherapy outcome.</p>Experimental Design:<p>Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence (mIF) in primary colorectal cancers with d-MMR (<i>N</i> = 33) from patients treated with anti–PD-1 antibodies. By digital image analysis, density, ratio, intensity, and spatial distribution of PD-L1, PD-1, CD8, CD3, CD68, LAG3, TGFβR2, MHC-I, CD14, B2M, and pan-cytokeratin were computed. Feature selection was performed by regularized Cox regression with LASSO, and a proportional hazards model was fitted to predict progression-free survival (PFS).</p>Results:<p>For predicting survival among patients with MMR-d advanced colorectal cancer receiving PD-1 blockade, cell-to-cell distance measurements, but not cell densities or ratios, achieved statistical significance univariately. By multivariable feature selection, only mean number of PD-1<sup>+</sup> cells within 10 μm of a PD-L1<sup>+</sup> cell was significantly predictive of PFS. Dichotomization of this variable revealed that those with high versus low values had significantly prolonged PFS [median not reached (>83 months) vs. 8.5 months (95% confidence interval (95% CI), 4.7–NR)] with a median PFS of 28.4 months for all patients [adjusted HR (HR<sub>adj</sub>) = 0.14; 95% CI, 0.04–0.56; <i>P</i> = 0.005]. Expression of PD-1 was observed on CD8<sup>+</sup> T cells; PD-L1 on CD3<sup>+</sup> and CD8<sup>+</sup> T lymphocytes, macrophages (CD68<sup>+</sup>), and tumor cells.</p>Conclusions:<p>In d-MMR colorectal cancers, PD-1<sup>+</sup> to PD-L1<sup>+</sup> receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.</p></div>