Data from Immune marker spatial distribution and clinical outcome after PD-1 blockade in mismatch repair-deficient, advanced colorectal carcinomas

AbstractPurpose: Targeting the PD-1/PD-L1 interaction has led to durable responses in fewer than half of patients with mismatch repair-deficient (MMR-d) advanced colorectal cancers (CRC). Immune contexture, including spatial distribution of immune cells in the tumor microenvironment, may predict immunotherapy outcome. Patients and Methods: Immune contexture and spatial distribution, including cell-to-cell distance measurements, were analyzed by multiplex immunofluorescence in primary CRCs with d-MMR (N=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). Results: For predicting survival among patients with MMR-d advanced CRC 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+ cells within 10μm of a PD-L1+ cell was significantly predictive of progression-free survival (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% CI: 4.7-NR) with a median PFS of 28.4 months for all patients HRadj= 0.14, 95% CI: 0.04, 0.56; p=0.005. Expression of PD-1 was observed on CD8+ T-cells; PD-L1 on CD3+ and CD8+ T-lymphocytes, macrophages (CD68+) and tumor cells. Conclusions: In d-MMR CRCs, PD-1+ to PD-L1+ receptor to ligand proximity is a potential predictive biomarker for the effectiveness of PD-1 blockade.