Clin Cancer Res. 2023 Aug 11:CCR-23-1109. doi: 10.1158/1078-0432.CCR-23-1109. Online ahead of print.
ABSTRACT
PURPOSE: 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.
PMID:37566222 | DOI:10.1158/1078-0432.CCR-23-1109
