Περίληψη:
Background: Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Methods: Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). Results: We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. Conclusion: This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Συγγραφείς:
Papalampros, A.
Vailas, M.
Ntostoglou, K.
Chiloeches, M.L.
Sakellariou, S.
Chouliari, N.V.
Samaras, M.G.
Veltsista, P.D.
Theodorou, S.D.P.
Margetis, A.T.
Bergonzini, A.
Karydakis, L.
Hasemaki, N.
Havaki, S.
Moustakas, I.I.
Chatzigeorgiou, A.
Karamitros, T.
Patsea, E.
Kittas, C.
Lazaris, A.C.
Felekouras, E.
Gorgoulis, V.G.
Frisan, T.
Pateras, I.S.
Λέξεις-κλειδιά:
CD47 antigen; regulator protein; signal regulatory protein alpha; unclassified drug, antigen expression; Article; cell aging; clinical article; controlled study; cytotoxicity; gene expression; histopathology; human; human cell; human tissue; immune response; immunoassay; immunohistochemistry; lymphocytic infiltration; neoadjuvant chemotherapy; pancreas adenocarcinoma; phenotype; protein expression; protein interaction; signal transduction; spatial analysis; T lymphocyte; T lymphocyte subpopulation; tumor localization; tumor microenvironment; upregulation
