Immuno-Interface Score to Predict Outcome in Colorectal Cancer Independent of Microsatellite Instability Status

Abstract

Tumor-associated immune cells have been shown to predict patient outcome in colorectal (CRC) and other cancers. Spatial digital image analysis-based cell quantification increases the informative power delivered by tumor microenvironment features and leads to new prognostic scoring systems. In this study we evaluated the intratumoral density of immunohistochemically stained CD8, CD20 and CD68 cells in 87 cases of CRC (48 were microsatellite stable, MSS, and 39 had microsatellite instability, MSI) in both the intratumoral tumor tissue and within the tumor-stroma interface zone (IZ) which was extracted by a previously developed unbiased hexagonal grid analytics method. Indicators of immune-cell gradients across the extracted IZ were computed and explored along with absolute cell densities, clinicopathological and molecular data, including gene mutation (BRAF, KRAS, PIK3CA) and MSI status. Multiple regression modeling identified (p < 0.0001) three independent prognostic factors: CD8+ and CD20+ Immunogradient indicators, that reflect cell migration towards the tumor, were associated with improved patient survival, while the infiltrative tumor growth pattern was linked to worse patient outcome. These features were combined into CD8-CD20 Immunogradient and immuno-interface scores which outperformed both tumor-node-metastasis (TNM) staging and molecular characteristics, and importantly, revealed high prognostic value both in MSS and MSI CRCs.

Tumor-Infiltrating Lymphocytes in Colorectal Cancer: The Fundamental Indication and Application on Immunotherapy

“…The group reported that MSI-H and MSS patients showed similar stromal CD8 + T cell densities and there was a significant increase in the density of CD8 + T cells within the tumor glands in MSI patients, in both the core and invasive margin of tumor (all p < 0.05) (47). The same conclusion was also found in the study of Smedt et al, which identified high numbers of intra-epithelial CD8 + cells in MSI compared with MSS tumors (48,49).…”

“…However, another report has given a complex interpretation of the roles of TIBs in CRC (49). It was observed that CD8 + and CD20 + immunogradient indicators, that reflect cell migration towards the tumor, were associated with improved patient survival, while the infiltrative tumor growth pattern was linked to worse patient outcomes.…”

Role of AI and digital pathology for colorectal immuno-oncology

“…Deep learning (DL) and ML-based approaches were explored for predicting MSI status [52][53][54][55][56][57][58][59][60][61][62][63][64], genetic alterations, CRC pathways, and high mutation density (HMD) [55,59] and tumour mutation burden (TMB) [65] from H&Estained histology slides. Few of these studies are automatically predicting survival based on immune cell densities directly from H&E image, IHC and gene expression data [66][67][68][69][70][71]. Details of these studies and their findings are reviewed in the subsequent sections.…”

Machine-Learning–Based Evaluation of Intratumoral Heterogeneity and Tumor-Stroma Interface for Clinical Guidance

“…More importantly, these statistically defined indicators add new dimensionality to the assessment of TIL densities within the IM and other TME compartments and have demonstrated strong independent prognostic value in breast and colorectal cancer patients. 13,24,25 A set of indicators were reported 26 based on spatial distributions and proximities between lymphocytes and/or cancer cells in breast cancer hematoxylin and eosin (H&E) WSIs. The method allowed quantification of the immune abundance (lymphocyte fractions to other cells) and immune spatial scores (clusters/hotspots) formed by lymphocytes and/or cancer cells within tumor regions.…”

“…Farchoukh et al 37 reported CD8 þ T-cell density by DIA and intratumoral budding by visual assessment in pretreatment biopsies of rectal adenocarcinoma as independent predictive biomarkers of response to neoadjuvant therapy. Nestarenkaite at al 25 proposed a prognostic Immuno-Interface Score for colorectal cancer survival probability based on independent contributions of CD8 and CD20 immunogradients along with the invasive growth pattern determined by pathologists' visual assessment; this approach outperformed evaluation of tumor budding alone.…”