Abstract 4262: AI-driven analysis of collagen characteristics in the tumor immune microenvironment predicts immune checkpoint inhibitors treatment responsiveness in gastric cancer
Authors: Kim Minji , Redekop Ekaterina , Choi Yoonho , Lee Sung Hak , Cheong Jae-Ho , Aoki Yu , Shitara Kohei , Hwang Tae Hyun 
Published: March 2024

Abstract
Background: Recent studies indicate a correlation between increased stromal composition in tumors and resistance to immune checkpoint inhibitors (ICIs) across various cancer types. Specifically, the extracellular matrix (ECM) within the stromal compartment significantly influence the tumor microenvironment, affecting cancer cell proliferation and immune cell recruitment. However, identifying and quantifying the ECM at the collagen fiber level in whole slide images (WSIs) is challenging due to its inherent heterogeneity and complexity. In this work, we utilized statistical analysis and a deep learning (DL)-based approach to identify and assess collagen in the ECM, examining its characteristics in relation to the ICIs treatment response in gastric cancer.
Methods: We analyzed 116 WSIs of hematoxylin and eosin (H&E) stained slides before ICIs treatment from three institutions. Responders were defined as those with a complete response or partial response (N=18); those with stable disease (SD) (N=34) or progressive disease (PD) (N=64) were considered non-responders (N=98). For non-responders, post-treatment H&E slides were available for 21 patients; SD (N=5) and PD (N=16). We applied a DL-based second harmonic generation (SHG) synthesis algorithm to tumor regions identified by a tumor detection model. We then calculated various collagen properties, including volume, fiber orientation and alignment, waviness, straightness, and fiber thickness, based on collagen fiber centerlines extracted from the generated SHG images. An attention-based multiple instance learning (ABMIL) model was trained to automatically predict the treatment response solely based on collagen features. The dataset of 116 pre-treatment slides was divided into training and validation subsets using stratified 3-fold cross-validation. The area under the curve (AUC) was used to assess the performance of the trained models.
Results: Collagen fiber features were significantly associated with ICIs response. Notably, ICIs responders have a decrease in collagen waviness and fiber orientation variation (p-value&lt;0.05, by Mann-Whitney U test). Among non-responders, the PD group showed a statistical decrease in waviness after treatment (p-value&lt;0.05, by Mann-Whitney U test). The ABMIL model achieved a mean AUC score of 0.823, with a standard deviation of 0.023.
Conclusion: This study provides a comprehensive analysis of collagen in the ECM, and its properties in relation to gastric cancer ICIs response within Tumor Immune Microenvironment. We also developed a model using collagen features and demonstrated high accuracy in predicting treatment response.
Citation Format: Minji Kim, Ekaterina Redekop, Yoonho Choi, Sung Hak Lee, Jae-Ho Cheong, Yu Aoki, Kohei Shitara, Tae Hyun Hwang. AI-driven analysis of collagen characteristics in the tumor immune microenvironment predicts immune checkpoint inhibitors treatment responsiveness in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4262.