MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

Fraune, Christoph; Burandt, Eike; Simon, Ronald; Hube‐Magg, Claudia; Makrypidi‐Fraune, Georgia; Kluth, Martina; Büscheck, Franziska; Höflmayer, Doris; Blessin, Niclas C.; Mandelkow, Tim; Li, Wenchao; Perez, Daniel; Izbicki, Jakob R.; Wilczak, Waldemar; Sauter, Guido; Schrader, Jörg; Neipp, Michael; Mofid, Hamid; Daniels, Thies; Isbert, C.; Clauditz, Till S.; Steurer, Stefan

doi:10.1245/s10434-020-08209-y

Cited by 23 publications

(24 citation statements)

References 66 publications

(89 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MSI has been reported in some studies to occur in 0%‐22% of unselected cases when IHC was used to assess MMR deficiency, and in 0%‐17% in reports utilizing PCR‐based methods 3,4 . The histological presence of tumor‐infiltrating lymphocytes has been linked to tumor phenotype as well as favorable patient outcomes or response to therapy in various tumor types 3,7 . MSI is associated with increased tumor‐infiltrating lymphocytes providing indirect evidence for the role of the antitumoral immune response 3,8,9 .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, tumor heterogeneity can be problematic as it undermines accurate molecular diagnostics and may diminish the success of targeted therapies. Despite these apparent barriers, recent studies ascertain that MSI occurs early in PDAC and that immunohistochemical MMR analysis on limited biopsy or cytology material may be sufficient to estimate the MMR status of the entire cancer mass 3 …”

Section: Discussionmentioning

confidence: 99%

“…3,4 The histological presence of tumor-infiltrating lymphocytes has been linked to tumor phenotype as well as favorable patient outcomes or response to therapy in various tumor types. 3,7 MSI is associated with increased tumorinfiltrating lymphocytes providing indirect evidence for the role of the antitumoral immune response. 3,8,9 The US Food and Drug Administration (FDA) recently furthered the endorsement of the immune checkpoint inhibitor pembrolizumab for patients with advanced tumor malignancy that is microsatellite instability (MSI)-high or mismatch repair (MMR) deficient.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, even postoperatively, reported disease recurrence soars at 80%‐85% of cases. The majority of patients will inevitably expire due to their disease as less than 5% of patients will survive more than 5 years following surgery 3 …”

Section: Introductionmentioning

confidence: 99%

“…The majority of patients will inevitably expire due to their disease as less than 5% of patients will survive more than 5 years following surgery. 3 Pancreatic cancer is very difficult to treat owing largely to gene instability and intratumoral genetic heterogeneity. New insights in the field suggest that epigenetic changes may play a role in the mechanism underlying tumoral heterogeneity, altering gene expression, and defining the malignant PDAC phenotypes.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

Teodosescu

Chan

Elder

et al. 2021

Diagnostic Cytopathology

View full text Add to dashboard Cite

Introduction Only 15%‐20% of newly diagnosed pancreatic ductal adenocarcinoma (PDAC) cases are surgically operable. Cytology samples may be the only source for guiding clinical management. Current research indicates that mismatch repair (MMR) status could be valuable for implementing novel treatment modalities. In this study, immunohistochemical (IHC) MMR protein expression on cytology cell blocks was compared with that of the correlating surgical resection specimens. Materials and Methods A retrospective review of 120 pancreatic solid tumor needle biopsies from 2016 to 2019 was performed, and 15 experimental cases were selected comprising of cellular (>100 tumor cells and >100 benign positive control cells that include benign ductal cells and/or lymphocytes) alcohol‐prefixed formalin‐fixed cytology cell blocks (CB), and corresponding subsequent surgical resections (Surg). The cases include 13 PDACs (87%), 1 (6.5%) low grade neuroendocrine tumor (PNET), and 1 (6.5%) acinar cell carcinoma (ACC). A routine four‐panel (MLH1, MSH2, MSH6, and PMS2) MMR IHC testing was performed. The percentage of protein expression was evaluated and compared between individual CB‐Surg pairs. Results About 8 of the 15 (53.3%) cytology cases showed matching protein expressivity with the surgical specimens for all four MMR markers (Table 1). The remaining 7 pairs (46.7%) appeared to have a partial concordance, including 6 values for which a surgical marker showed less expression, and 13 values for which a cytological marker showed less expression. A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens N = 15 MLH1 MSH2 MSH6 PMS2 CB Surg CB Surg CB Surg CB Surg PDAC>80%>80%>80%>80%>80%>80%>80%>80%PDAC20%‐30%<20%50%‐60%60%‐70%30%‐40%30%‐40%40%‐50%<20%PDAC<20%<20%<20%50%‐60%<20%<20%20%‐30%<20%PDAC>80%>80%>80%>80%50%‐75%50%‐75%>80%>80%PDAC<20%<20%>80%>80%<20%<20%>80%>80%PDAC>80%>80%60%‐70%40%‐50%60%‐70%50%‐60%60%‐70%40%‐50%PDAC<20%<20%>80%>80%>80%>80%<20%<20%PDAC<20%<20%25%‐50%25%‐50%25%‐50%25%‐50%<20%<20%ACC<10%60%‐70%50%‐60%>90%<10%<10%<10%60%‐70%PNET25%‐50%25%‐50%>80%>80%25%‐50%25%‐50%50%‐75%50%‐75%PDAC40%‐50%>80%50%‐60%>80%>80%>80%40%‐50%>80%PDAC50%‐75%50%‐75%50%‐75%50%‐75%50%‐75%50%‐75%40%‐50%40%‐50%PDAC40%‐50%>80%40%‐50%>80%<20%>80%Tumor cell loss>80%PDAC>80%>80%>80%>80%50%‐75%50%‐75%>80%>80%PDACTumor cell loss50%‐75%40%‐50%>80%50%‐75%>80%Tumor cell loss50%‐75% Notes: Bold represents full concordance between cytology and surgical. Italics represents less expression on surgical samples. Bold italics indicates less expression on cytology samples. Conclusion Cytology CB MMR protein panel testing could be a useful consideration for inoperable patients who would benefit from medical therapy such as immune checkpoint inhibition. However, the cellularity and overall quality of the CB is expected to be paramount in obtaining satisfactory IHC MMR results. The MMR results could be more confidently trusted when the staining is int...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

Teodosescu

Chan

Elder

et al. 2021

Diagnostic Cytopathology

View full text Add to dashboard Cite

show abstract

Colonic epithelial cathelicidin (LL‐37) expression intensity is associated with progression of colorectal cancer and presence of CD8⁺ T cell infiltrate

Porter

Murray

Alnabulsi

et al. 2021

The Journal of Pathology CR

View full text Add to dashboard Cite

Colorectal cancer (CRC) remains a leading cause of cancer mortality. Here, we define the colonic epithelial expression of cathelicidin (LL‐37) in CRC. Cathelicidin exerts pleotropic effects including anti‐microbial and immunoregulatory functions. Genetic knockout of cathelicidin led to increased size and number of colorectal tumours in the azoxymethane‐induced murine model of CRC. We aimed to translate this to human disease. The expression of LL‐37 in a large (n = 650) fully characterised cohort of treatment‐naïve primary human colorectal tumours and 50 matched normal mucosa samples with associated clinical and pathological data (patient age, gender, tumour site, tumour stage [UICC], presence or absence of extra‐mural vascular invasion, tumour differentiation, mismatch repair protein status, and survival to 18 years) was assessed by immunohistochemistry. The biological consequences of LL‐37 expression on the epithelial barrier and immune cell phenotype were assessed using targeted quantitative PCR gene expression of epithelial permeability (CLDN2, CLDN4, OCLN, CDH1, and TJP1) and cytokine (IL‐1β, IL‐18, IL‐33, IL‐10, IL‐22, and IL‐27) genes in a human colon organoid model, and CD3+, CD4+, and CD8+ lymphocyte phenotyping by immunohistochemistry, respectively. Our data reveal that loss of cathelicidin is associated with human CRC progression, with a switch in expression intensity an early feature of CRC. LL‐37 expression intensity is associated with CD8+ T cell infiltrate, influenced by tumour characteristics including mismatch repair protein status. There was no effect on epithelial barrier gene expression. These data offer novel insights into the contribution of LL‐37 to the pathogenesis of CRC and as a therapeutic molecule.

show abstract

Advances in immunotherapy for pancreatic ductal adenocarcinoma

Miyazawa

Katsuda

Kawai

et al. 2021

J Hepato Biliary Pancreat

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a recalcitrant disease with 5-year survival at less than 10%. 1 Meanwhile, recent innovative advances in immunotherapy, particularly immune checkpoint inhibitors (ICIs), have had significant clinical benefit in other cancers (Table 1). 2 The main reason why PDAC is refractory to immunotherapies including ICIs is that it is a so-called "cold tumor." 3,4 The tumor microenvironment (TME) in cold tumors, such as PDAC and glioblastomas, is rich in suppressive immune cells, but there are few infiltrations of cytotoxic immune cells with abundant cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM). 5 Conversely, "hot tumors," including melanomas and non-small cell lung cancer, have a TME with T-cell infiltration and they tend to respond well to ICIs. 6 Tumor-infiltrating lymphocytes (TILs) in PDAC can also be used to predict its prognosis, [7][8][9] indicating that PDAC immunotherapy has

show abstract

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

Cited by 23 publications

References 66 publications

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

Colonic epithelial cathelicidin (LL‐37) expression intensity is associated with progression of colorectal cancer and presence of CD8⁺ T cell infiltrate

Advances in immunotherapy for pancreatic ductal adenocarcinoma

Contact Info

Product

Resources

About

MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes

Cited by 23 publications

References 66 publications

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

A correlation study of mismatch repair immunohistochemical protein expression of pancreatic solid tumors in cytology cell blocks and matching surgical specimens

Colonic epithelial cathelicidin (LL‐37) expression intensity is associated with progression of colorectal cancer and presence of CD8+ T cell infiltrate

Advances in immunotherapy for pancreatic ductal adenocarcinoma

Contact Info

Product

Resources

About

Colonic epithelial cathelicidin (LL‐37) expression intensity is associated with progression of colorectal cancer and presence of CD8⁺ T cell infiltrate