Abstract C043: Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the tumor microenvironment

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with poor prognosis and treatment options. Technological challenges in dissecting the immune constituents of the PDAC tumor microenvironment (TME) has limited our understanding of the complex disease mechanisms in vivo, which may in part explain the lack of novel therapeutics for this recalcitrant disease. Here, we performed spatial proteomics using the multiplexed ion beam imaging (MIBI) approach to quantify 36 spatial signatures in tissues from a cohort of twelve treatment naïve PDAC patients. We applied a deep learning segmentation algorithm to better resolve expression levels at the single cell resolution, and robustly stratify phenotypes through an iterative process of clustering and annotation, with expert visual validation. The combination of phenotypic quantification, functional marker evaluation within the cell types identified, as well as machine-learning based topic modeling to understand cellular neighborhoods, can better explain the cellular and functional components within the intricate PDAC TME. Our analysis revealed markedly lower B and effector T cell infiltration in the treatment-naive TME of patients who eventually relapsed to date following adjuvant chemotherapy. We additionally observed the enrichment of myeloid cell populations, including tumor-associated macrophages and neutrophils, associated with PDAC tumorigenesis and worse prognosis. A deeper analysis of our functional protein expression exhibited the enrichment of GATA3 in regulatory T cells in relapsed patients, a marker which has been associated with increased accumulation and infiltration of Tregs at inflammatory sites. Our study demonstrates the importance of a targeted dissection of the spatially orchestrated immune responses and dysregulation associated with PDAC, and exemplifies how a deeper understanding of the immune and tumor components and functional aspects in situ can help improve our understanding for patients with this disease. Citation Format: Jason Yeung, Yunhao Bai, Yao Yu Yeo, Huaying Qiu, Bokai Zhu, Lara R. Heij, Enas Abu Shah, Garry P. Nolan, Shivan Sivakumar, Sizun Jiang. Spatial proteomic immune profiling of pancreatic ductal adenocarcinoma and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C043.