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Background: In recent years, a relationship between the tumor microenvironment (TME) and patient response to targeted cancer immunotherapy has been suggested. We applied machine-learning algorithms on H&E stained tissue to study the TME in metastatic non-small cell lung cancer (NSCLC) patients. Our goal was to identify digital pathology (DP) features associated with outcome under combination treatment or monotherapy with atezolizumab (atezo), an anti-PD-L1 therapy, and relate those features to other data modalities. We analyzed patient data from two phase 3 clinical trials, OAK (docetaxel versus atezo in 2L+ NSCLC) and IMpower150 (bevacizumab, carboplatin, and paclitaxel (BCP) versus BCP+atezo (ABCP) in advanced 1L non-squamous NSCLC). Methods: As part of our effort to build a DP-based tumor-immune microenvironment atlas, digitized H&E images were registered onto the PathAI research platform. Over 200K annotations from 90 pathologists were used to train convolutional neural networks (CNNs) that classify slide-level human-interpretable features (HIFs) of cells and tissue structures from images and deployed on images from OAK and IMpower150. HIFs and PD-L1 status were associated with outcome in all samples in each arm in OAK and results were validated in IMpower150, using Cox proportional hazard models. Bulk RNAseq was run using samples extracted from the same area as the H&E slide. Results: We identified a composite feature capturing the ratio of immune cells to fibroblasts in the stroma predictive of both overall survival (OS) (HR=0.74 p=0.0046) and progression-free survival (PFS) (HR=0.87 p=0.14). While patients primarily benefit from atezo if they are PD-L1 high, we found that even PD-L1 negative patients benefited from atezo when enriched for this feature (22C3 PD-L1 assay: OS HR=0.59 p=0.015, PFS HR=0.8 p=0.25; SP142 PD-L1 assay: OS HR=0.74 p=0.12, PFS HR=0.88 p=0.45). We thus recognized a DP feature that was predictive for positive outcome with atezo treatment, independent of PD-L1 levels. This association was then validated in IMpower150 comparing ABCP to BCP, both overall (OS HR=0.69 p=0.012) and in PD-L1 negative patients (SP263 assay OS HR=0.56 p=0.034). Integrating with RNAseq, patients enriched for this DP feature showed similar enrichment for B and T gene signatures and depletion in CAF-related gene signatures, thus showing the harmonization of TME between different data modalities. Conclusions: Using a deep learning-based assay for quantifying pathology features of the TME from H&E images in two NSCLC trials, we identified a novel biomarker predictive of outcome to PD-L1 targeting therapy, even in PD-L1 low & negative patients. Importantly, our work shows how different data modalities (DP, gene expression) can be integrated to further our understanding of the TME. Citation Format: Aditi Qamra, Minu K. Srivastava, Eloisa Fuentes, Ben Trotter, Raymond Biju, Guillaume Chhor, James Cowan, Steven Gendreau, Webster Lincoln, Lisa McGinnis, Luciana Molinero, Namrata S. Patil, Amber Schedlbauer, Katja Schulze, Adam Stanford-Moore, Laura Chambre, Ilan Wapinski, David S. Shames, Hartmut Koeppen, Stephanie Hennek, Jane Fridlyand, Jennifer M. Giltnane, Assaf Amitai. Digital pathology based prognostic & predictive biomarkers in metastatic non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5705.