Abstract
Small bowel adenocarcinoma (SBA) is a rare malignancy marked with a poor prognosis. The cellular and proteomic heterogeneity within the tumor immune microenvironment (TIME) of SBA is a likely driver of prognosis, disease progression and response to therapy. We have addressed a major gap in knowledge of the TIME in SBA using highly multiplexed, protein imaging of the SBA tumor-immune ecosystem generating a comprehensive, single-cell level, spatial, proteomic atlas of TIME in > 600,000 cells from 136 tumor and matched normal samples from clinically and genomically annotated SBA patients (N=37). The SBA TIME Atlas informs on spatial distribution and interactions of tumor-intrinsic processes, diverse immune cell types, immune checkpoints, and vascularization. Enrichment of proliferating epithelial tissue, stem cells, and likely pro-tumor immune signatures in the tumor niche is contrasted by the representation of naïve and early-effector T-cells in the epithelial compartments of adjacent normal tissues. Epithelial-stem-immune cell spatial architectures within tumor and matched-normal niches were strongly associated with patient survival, suggesting malignancy is driven by spatial architecture beyond the tumor microenvironment. The blueprints of therapeutically actionable immune checkpoints at the interface between epithelial and microenvironmental T-cells as well as macrophages have established a guideline for precision immunotherapies tailored to the TIME composition in SBA. We expect that this SBA atlas will contribute to a deeper understanding of the immune contexture in this rare disease as well as other gastrointestinal cancers and help guide future precision immune-oncology strategies.
Competing Interest Statement
Gordon Mills: Relationship: Consultant/Scientific Advisory Board Companies: Amphista, Astex, AstraZeneca, BlueDot, Ellipses Pharmaceuticals, ImmunoMET, Ionis, Leapfrog Bio, Bruker/Nanostring, Neophore, Nerviano, Nuvectis, Pangea, PDX Pharmaceuticals, Qureator, Rybodyne, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals **= travel reimbursement only Relationship: Stock/Options/Financial Companies: Bluedot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, RyboDyne, SignalChem Lifesciences, Tarveda, Turbine Relationship: Licensed Technology Companies: HRD assay to Myriad Genetics DSP to Nanostring Foundation support: Adelson Medical Research Foundation, Breast Cancer Research Foundation, Komen Research Foundation, Ovarian Cancer Research Foundation, Prospect Creek Foundation Sponsored research AstraZeneca, Zentalis, Nanostring, Ionis (Provision of tool compounds) Clinical trials support (funding or in kind) AstraZeneca, Genentech, GSK, Lilly Entire List Amphista, Astex, AstraZeneca, BlueDot, Ellipses Pharmaceuticals, ImmunoMET, Ionis, Leapfrog Bio, Bruker/Nanostring, Neophore, Nerviano, Nuvectis, Pangea, PDX Pharmaceuticals, Qureator, Rybodyne, Signalchem Lifesciences, Tarveda, Turbine, Zentalis Pharmaceuticals; Stock/Options/Financial Companies: Bluedot, Catena Pharmaceuticals, ImmunoMet, Nuvectis, RyboDyne, SignalChem Lifesciences, Tarveda, Turbine; Licensed Technology Companies: HRD assay to Myriad Genetics DSP to Nanostring; Foundation support: Adelson Medical Research Foundation, Breast Cancer Research Foundation, Komen Research Foundation, Ovarian Cancer Research Foundation, Prospect Creek Foundation; Sponsored research; AstraZeneca, Zentalis, Nanostring, Ionis (Provision of tool compounds); Clinical trials support (funding or in kind) AstraZeneca, Genentech, GSK, Lilly Zeynep Dereli Shareholder: ViVoz Biolabs