Abstract Purpose: Tumor immune cell infiltration patterns in the tumor microenvironment serve as prognostic biomarkers in metastatic colorectal cancer (mCRC). This study analyzed the spatially resolved tumor immune microenvironment for prognostic and predictive impact in patients with RAS wildtype mCRC receiving FU/FA ± Pmab maintenance after Pmab + FOLFOX induction (PanaMa AIO KRK0212; NCT01991873). Patients and Methods: Twelve immune parameters (lymphocyte markers: CD3, CD8, CD45RO, FOXP3, CD20, Granzyme B, Perforin; immune checkpoints: PD-1, PD-L1, IDO1, LAG3; monocyte marker CD163) were quantified in spatially resolved tumor and stroma regions (invasive-margin Inv, center Cen) on tissue microarrays from available surgical resections using digital pathology. Prognostic and predictive associations were assessed using percentile cutoffs, immunoscore (IS), PD-L1 CPS, and an immunoactivation score (IAS). Median progression-free (PFS) and overall survival (OS) were estimated by Kaplan-Meier-method, log rank test and Cox regression. Results: In 194 patients, low CD163 and high PD-1 in the tumor center were independent prognostic factors for prolonged PFS, while high central LAG3 was associated with improved OS. Pmab maintenance conferred PFS benefit in patients with low CD3InvStr, CD8Inv, LAG3CenTum, CD163CenTum, IS, and high CD45ROCen. CD45ROCen-high and LAG3Cen-low also predicted OS benefit. A positive IAS (≥2 predictive markers) identified patients deriving significant PFS (HR 0.50, 95% CI 0.32–0.76; P0.001) and OS (HR 0.54, 95% CI 0.33–0.86; P=0.009) benefit from Pmab. Conclusions: Immune microenvironment factors, including CD3, CD8, CD163, LAG3, CD45RO, IS, and IAS, predict benefit from Pmab maintenance, suggesting immune activation as a key component of anti-EGFR efficacy.
Ballhausen et al. (Wed,) studied this question.