Abstract
Abstract Introduction: The prognosis of gastrointestinal malignancies has improved significantly with the introduction of neoadjuvant therapy (neoTx). For rectal (RCa) and esophageal adenocarcinoma (OCa), neoTx has become the standard of care, resulting in tumor-downsizing and significantly prolonged patient survival. However, the effects of neoTx on the topographical interactions between different populations of tumor-infiltrating immune cells, the degree of intratumoral immune infiltration, the distance to tumor cells, as well as their spatial interactions with other important features of the tumor microenvironment (TME), are still unknown. In this cross-cancer histopathological profiling of the microenvironment of rectal and esophageal tumors, we aim to investigate the local effects of cytotoxic agents and determine whether these correspond to the pathological changes observed in pancreatic cancer (PCa). Methods In this study, we employed multiplex immunohistochemistry (mIHC) based on tyramide signal amplification (TSA) using OPAL® dyes and a customized 6-plex approach to characterize tumor-associated stromal features (CD11c, CD34, NCAM, PGP9.5, aSMA, PanCK) as well as tumor-infiltrating lymphoid (CD3, CD4, CD8, CD20, FOXP3, PanCK) and myeloid cell subsets (CD11b, CD33, CD68, CD208, HLA-DR, PanCK). FFPE samples from 60 neoadjuvantly treated RCa and 40 OCa patients and a matched cohort of primary resected patients were included in the analysis. Results In PCa, neoTx alters the TME by depleting pro-tumorigenic immune cells, such as myeloid-derived suppressor cells (MDSC) and regulatory T cells, and suppressing tumor-associated stromal activation, neural invasion, and microangiogenesis. In our current study, we generated three standardized 6-plex panels for comprehensive histopathologic analysis of the immune architecture and associated stromal features of neoadjuvantly treated RCa and OCa patients compared with primary resected patients. Lymphoid subpopulations included Th-cells, cytotoxic T-cells, regulatory T-cells, and B-cells, while MDSC, dendritic cells, M1- and M2-macrophages were analyzed in the myeloid panel within the same FFPE slide. Conclusion: Our findings highlight new differential cell identities in neoTx-treated PCa patients and confirm their suitability for optimizing future clinical immunotherapy trials. Our current approach validates multiplex-IHC approaches for histological profiling of FFPE tumor samples in RCa and OCa and demonstrates the importance of a deep topographic characterization to understand the TME composition of gastrointestinal malignancies after neoTx. Citation Format: Leonard Richter. Multiplex analysis of pancreatic, oesophageal and rectal adenocarcinoma: A cross-cancer approach on the impact of neoadjuvant therapy on the tumour microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2023 Oct 1-4; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Immunol Res 2023;11(12 Suppl):Abstract nr B048.
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