Abstract
Immunotherapeutic modalities are currently revolutionizing cancer treatment. In pancreatic cancer, however, early clinical trials have been disappointing. The optimization of immunotherapeutic strategies requires better understanding of the inflammatory tumor microenvironment. Therefore, the aim of our study was to perform a detailed in situ description of lymphocyte infiltration patterns in resected pancreatic and other periampullary cancers. Multiplexed immunofluorescence imaging was applied to tissue microarrays with tumors from a cohort of 175 patients with resected periampullary adenocarcinoma. A panel of immune cell markers including CD4, CD8α, FoxP3, CD20, CD45RO and pan-cytokeratin was applied to allow for simultaneous spatial analysis of multiple lymphocyte populations. The majority of lymphocyte populations were significantly more abundant in intestinal (I-type) compared to pancreatobiliary (PB-type) tumors. Hierarchical cluster analysis revealed several immune cell signatures of potential clinical relevance. Notably, in the stromal compartment of PB-type tumors, high infiltration of B cells, CD8α+ CD45RO+ and single-positive CD4+ T cells, but low levels of FoxP3+ CD45ROhigh and single-positive CD8α+ T cells were associated with improved overall survival (OS). The study also defined prognostic relevant topographical patterns of lymphocytic infiltration, in particular proximity of CD8α+ cells to cancer cells. Moreover, the presence of lymphocytes with potential T-helper capacities (CD4+ ) in the nearest vicinity to CD8α+ cells was associated with a prolonged OS. Our data demonstrate that the composition and clinical impact of immune infiltrates in periampullary adenocarcinoma differ by morphological type as well as localization. Furthermore, spatial in situ analysis identified potential immunological mechanisms of prognostic significance.
Highlights
Periampullary adenocarcinoma, including pancreatic cancer, is a collective term for cancers arising around the ampulla of Vater
Individual marker expression levels in each cell were used to identify TIL subtypes: CD4+ single-positive cells, CD4+CD45RO+cells, CD4+FoxP3+, single-positive CD8+ cells, CD8α+CD45RO+ (referred to as activated (a)
Since FoxP3+CD45ROlow cells were difficult to distinguish from FoxP3+ cancer cells in the tumor compartment, the analysis of FoxP3+CD45ROlow lymphocytes was restricted to the stromal compartment
Summary
Periampullary adenocarcinoma, including pancreatic cancer, is a collective term for cancers arising around the ampulla of Vater. The periampullary region is a complex region which is composed of distinct anatomical structures: the head of the pancreas, distal common bile duct, second portion of the duodenum and ampulla of Vater. Periampullary adenocarcinomas are currently classified by their anatomic location of origin according to the seventh edition of the American Joint Committee on Cancer staging system.[1] They can be divided into two subgroups based on morphology, either intestinal type (I-type) or pancreatobiliary type (PB-type), and there is increasing evidence that morphology is a more important determinant of survival than anatomical origin.[2,3,4,5] Survival rates remain dismally low for this group of patients, with 5-year overall survival (OS) rates of around 6%,6 partly due to late presentation of the disease, and because both conventional and targeted therapies have shown limited efficacy. The only curative treatment of pancreatic and periampullary adenocarcinomas is surgery, only 15–20% of the patients are eligible for surgery at the time of Analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma
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