Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma

Heby, Margareta; Lundgren, Sebastian; Nodin, Björn; Elebro, Jacob; Eberhard, Jakob; Jirström, Karin

doi:10.1186/s12967-018-1444-4

Cited by 9 publications

(6 citation statements)

References 37 publications

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“…In I‐type tumors, dMMR status was associated with higher lymphocyte infiltration. It has previously been shown, with single stain immunohistochemistry, that CD8 + T cells are more abundant in dMMR I‐type tumors, but the present study provides a much more detailed phenotyping. dMMR leads to hypermutation and increased neoepitope formation, in turn potentially leading to a more efficient immunological response and increased infiltration of immune cells into the tumor.…”

Section: Discussionmentioning

confidence: 82%

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Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Lundgren

Elebro

Heby

et al. 2020

Intl Journal of Cancer

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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 + CD45RO high 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.Additional Supporting Information may be found in the online version of this article.

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Section: Discussionmentioning

confidence: 82%

“…In 34 cases, paired‐samples from benign tissue was available, 9 from I‐type tumors and 25 from PB‐type tumors. Mismatch repair status was assessed by immunohistochemistry as previously described …”

Section: Methodsmentioning

confidence: 99%

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Lundgren

Elebro

Heby

et al. 2020

Intl Journal of Cancer

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“…In line with these findings, a previous paper using the same methodology demonstrated that T and B lymphocytes are also more abundant in I-type tumors ( 12 ). These findings are also supported by the considerably larger proportion of mismatch repair deficiency in I-type tumors ( 15 ), a feature that is often associated with a higher tumor mutational burden and tumor immunogenicity. Contrastingly, PB-type tumors may have properties that suppress immune cell infiltration and functionality.…”

Section: Discussionmentioning

confidence: 76%

“…Paired benign tissue was available from 34 cases, nine of which were I-type tumors and 25 PB-type tumors. Mismatch repair (MMR) deficiency was assessed as previously described (15).…”

Section: Study Cohortmentioning

confidence: 99%

Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

et al. 2020

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Background: The clinical management of pancreatic and other periampullary neoplasms remains challenging. In contrast to other cancer types, immunotherapies are largely ineffective, and the reason for the deprived immune response and the immune inhibiting cellular composition is only fragmentarily understood. The aim of this study was to comprehensively map the abundance, topographic distribution and spatial interaction of innate and innate-like immune cells in the tumor microenvironment of periampullary adenocarcinoma. Methods: Multiplexed immunofluorescent imaging was performed on tissue microarrays with tumors from a consecutive cohort of 175 patients with resected periampullary adenocarcinoma. To obtain a detailed spatial analysis of immune cell infiltration, two multiplex immune panels including antibodies against CD3, NKp46, CD56, CD68, CD163 and CD1a, CD208, CD123, CD15, CD68 and pancytokeratin were applied. Results: The infiltration of natural killer (NK) and NK-like T (NKT) cells was lower in malignant compared to benign tissue. NKT cells were more abundant in intestinal type compared to pancreatobiliary type tumors, and were associated with more favorable clinicopathological features and a prolonged survival. The interaction of NKp46 + NKT cells with macrophages was also associated with a prolonged survival. Conclusions: This study provides a comprehensive map of the innate immune landscape in periampullary adenocarcinoma. NK cells, and even more so NKT cells, are revealed to be central players in the local immune response in a clinically relevant context.

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“…At last follow-up, 137 patients were dead, and 124 had denoted recurrence. The median follow-up time for the entire cohort was 29.7 (range 1.9–185.1) months, and 86.1 (range 63.5–185.1) months for patients alive [39].…”

Section: Methodsmentioning

confidence: 99%

Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma

et al. 2019

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BackgroundTamoxifen treatment has previously been reported to confer life-prolonging effects in patients with advanced pancreatic cancer, and most evidently so in women. None of these trials did however include biomarkers, and the relevance of female hormone signaling in pancreatic or other periampullary adenocarcinoma remains largely unexplored. The aim of this study was to examine the extent and potential clinical significance of estrogen receptor-α (ER) and progesterone receptor (PR) expression in pancreatic and other periampullary cancers.MethodsER and PR expression was examined using immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, with long-term clinical follow-up. Non-parametric and Chi square tests were applied to examine the associations of stromal ER and PR expression with patient and tumor characteristics. Kaplan-Meier analysis and log rank test were applied to illustrate survival differences in relation to ER and PR expression. Cox regression proportional hazards models were applied to examine the associations between investigative factors and risk of death and recurrence, and to test for interactions between KRAS mutation status and hormone receptor expression in relation to survival.ResultsExpression of both ER and PR was more frequent in the tumor-associated stroma than in the epithelium. A significant prognostic interaction, independent of tumor morphology, was found between stromal PR expression and KRAS mutation status in relation to both overall and recurrence-free survival (pinteraction = 0.026 and pinteraction = 0.005), in particular in women (pinteraction = 0.002 and pinteraction = 0.005). Specifically, stromal PR expression was associated with a prolonged survival in patients with KRAS-mutated tumors, whereas the opposite was seen for KRAS wild-type tumors. The prognostic value of ER positivity was limited to the subgroup of women with tumors of pancreatic origin.ConclusionsThese results demonstrate that stromal PR rather than ER expression, together with KRAS mutation status, provides long-term prognostic information in patients with periampullary adenocarcinoma. Further study into the mechanistic basis for these observations may unveil important clues to the pathogenesis of these cancers and open up for the discovery of novel treatment options.

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Relationship between mismatch repair immunophenotype and long-term survival in patients with resected periampullary adenocarcinoma

Cited by 9 publications

References 37 publications

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Topographical Distribution and Spatial Interactions of Innate and Semi-Innate Immune Cells in Pancreatic and Other Periampullary Adenocarcinoma

Clinical significance of stromal ER and PR expression in periampullary adenocarcinoma

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