Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. Methods We used tissue microarray analysis to compare immune cell infiltration of different pancreaticobiliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis) and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We also analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice and the effects of all-trans retinoic acid (ATRA) on these processes. Results Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase⁺ and CD68⁺ cells compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8⁺, FoxP3⁺, CD56⁺, or CD20⁺ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8⁺ T cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8⁺ T cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8⁺ T cells, from patients with PDAC, had increased chemotaxis toward activated PSCs, which secrete CXCL12, compared with quiescent PSCs or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Conclusions Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8⁺ T cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective antitumor immune response.

We have profiled, for the first time, an evolving human metastatic microenvironment by measuring gene expression, matrisome proteomics, cytokine and chemokine levels, cellularity, extracellular matrix organization, and biomechanical properties, all on the same sample. Using biopsies of high-grade serous ovarian cancer metastases that ranged from minimal to extensive disease, we show how nonmalignant cell densities and cytokine networks evolve with disease progression. Multivariate integration of the different components allowed us to define, for the first time, gene and protein profiles that predict extent of disease and tissue stiffness, while also revealing the complexity and dynamic nature of matrisome remodeling during development of metastases. Although we studied a single metastatic site from one human malignancy, a pattern of expression of 22 matrisome genes distinguished patients with a shorter overall survival in ovarian and 12 other primary solid cancers, suggesting that there may be a common matrix response to human cancer. Significance: Conducting multilevel analysis with data integration on biopsies with a range of disease involvement identifies important features of the evolving tumor microenvironment. The data suggest that despite the large spectrum of genomic alterations, some human malignancies may have a common and potentially targetable matrix response that influences the course of disease. Cancer Discov; 8(3); 304–19. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 253

Background: The aim of the study was to develop a dedicated colorectal Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity (CR-POSSUM) equation for predicting operative mortality, and to compare its performance with the Portsmouth (P)-POSSUM model. Methods: Data were collected prospectively from 6883 patients undergoing colorectal surgery in 15 UK hospitals between 1993 and 2001. After excluding missing data and 93 patients who did not satisfy the inclusion criteria, 4632 patients (68·2 per cent) underwent elective surgery and 2107 had an emergency operation (31·0 per cent); 2437 operations (35·9 per cent) for malignant and 4267 (62·8 per cent) for non-malignant diseases were scored. Stepwise logistic regression analysis was used to develop an age-adjusted POSSUM model and a dedicated CR-POSSUM model. A 60 : 40 per cent split-sample validation technique was adopted for model development and testing. Observed and expected mortality rates were compared. Results: The operative mortality rate for the series was 5·7 per cent (387 of 6790 patients) (elective operations 2·8 per cent; emergency surgery 12·0 per cent). The CR-POSSUM, age-adjusted POSSUM and P-POSSUM models had similar areas under the receiver–operator characteristic curves. Model calibration was similar for CR-POSSUM and age-adjusted POSSUM models, and superior to that for the P-POSSUM model. The CR-POSSUM model offered the best overall accuracy, with an observed: expected ratio of 1·000, 0·998 and 0·911 respectively (test population). Conclusion: The CR-POSSUM model provided an accurate predictor of operative mortality. External validation is required in hospitals different from those in which the model was developed.

Cancer‐associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro‐ versus anti‐tumoural) in PDAC. We hypothesised that multiple CAF functional subtypes exist in PDAC, that contribute to stromal heterogeneity through interactions with cancer cells. Using molecular and functional analysis of patient‐derived CAF primary cultures, we demonstrated that human PDAC‐derived CAFs display a high level of inter‐ and intra‐tumour heterogeneity. We identified at least four subtypes of CAFs based on transcriptomic analysis, and propose a classification for human PDAC‐derived CAFs (pCAFassigner). Multiple CAF subtypes co‐existed in individual patient samples. The presence of these CAF subtypes in bulk tumours was confirmed using publicly available gene expression profiles, and immunostainings of CAF subtype markers. Each subtype displayed specific phenotypic features (matrix‐ and immune‐related signatures, vimentin and α‐smooth muscle actin expression, proliferation rate), and was associated with an assessable prognostic impact. A prolonged exposure of non‐tumoural pancreatic stellate cells to conditioned media from cancer cell lines (cancer education experiment) induced a CAF‐like phenotype, including loss of capacity to revert to quiescence and an increase in the expression of genes related to CAF subtypes B and C. This classification demonstrates molecular and functional inter‐ and intra‐tumoural heterogeneity of CAFs in human PDAC. Our subtypes overlap with those identified from single‐cell analyses in other cancers, and pave the way for the development of therapies targeting specific CAF subpopulations in PDAC. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Pancreatic ductal adenocarcinoma (PDAC) is the most common epithelial, exocrine pancreatic malignancy, i.e. accounting for more than 80% of the malignant neoplasms of the pancreas [ 1 x [1] Alexakis, N., Halloran, C., Raraty, M., Ghaneh, P., Sutton, R., and Neoptolemos, J.P. Current standards of surgery for pancreatic cancer. Br J Surg. 2004; 91: 1410–1427 Crossref | PubMed | Scopus (240) | Google Scholar See all References ] [1] . It remains the fourth most common cause of cancer-related death in the Western world [ 2 x [2] Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., and Thun, M.J. Cancer statistics, 2007. CA Cancer J Clin. 2007; 57: 43–66 Crossref | PubMed | Scopus (6785) | Google Scholar See all References ] [2] . The incidence of pancreatic cancer correlates with increasing age with a peak incidence of the disease occurring in the 65–75 year age group [ 3 x [3] Lowenfels, A.B. and Maisonneuve, P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006; 20: 197–209 Abstract | Full Text | Full Text PDF | PubMed | Scopus (287) | Google Scholar See all References ] [3] . Untreated metastatic pancreatic cancer has a median survival of 3–5 months and 6–10 months for locally advanced disease [ 4 x [4] O'Sullivan, A. and Kocher, H.M. Pancreatic cancer. Br Med J Clin Evid. 2007; 11: 409–437 Google Scholar See all References ] [4] . The majority of cases are diagnosed in the advanced stages, making curative therapy impossible and leading to poor prognosis and incidence equalling mortality [ 5 x [5] Li, D., Xie, K., Wolff, R., and Abbruzzese, J.L. Pancreatic cancer. Lancet. 2004; 363: 1049–1057 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1377) | Google Scholar See all References ] [5] . In the year 2000, there were 217,000 new cases of pancreatic cancer with 213,000 deaths worldwide, while in Europe there were 60,139 new patients with 64,801 deaths [ 6 x [6] Parkin, D.M., Bray, F.I., and Devesa, S.S. Cancer burden in the year 2000. The global picture. Eur J Cancer. 2001; 37: S4–66 Abstract | Full Text | Full Text PDF | PubMed | Google Scholar See all References ] [6] . In the UK, 7,152 new cases were seen with 7,250 deaths as a result of PDAC [ 7 x [7] Ghaneh, P., Costello, E., and Neoptolemos, J.P. Biology and management of pancreatic cancer. Gut. 2007; 56: 1134–1152 Crossref | PubMed | Scopus (11) | Google Scholar See all References ] [7] . PDAC affects more individuals inhabiting the Western/industrialized parts of the world; the highest incidence has been reported among Maoris in New Zealand, native Hawaiians and Black American populations, while people living in India and Nigeria have the lowest reported incidence [ 8 x [8] Boyle, P., Hsieh, C.C., Maisonneuve, P., La Vecchia, C., Macfarlane, G.J., and Walker, A.M. Epidemiology of pancreas cancer 1988. Int J Pancreatol. 1989; 5: 327–346 Crossref | PubMed | Scopus (108) | Google Scholar See all References , 9 x [9] Mack, T.M., Peters, J.M., Yu, M.C., Hanisch, R., Wright, W.E., and Henderson, B.E. Pancreas cancer is unrelated to the workplace in Los Angeles. Am J Ind Med. 1985; 7: 253–266 Crossref | PubMed | Scopus (27) | Google Scholar See all References ]. Being Jewish increases the risk of developing PDAC as compared to other religious faiths [ 10 x [10] Phillips, R.L., Garfinkel, L., Kuzma, J.W., Beeson, W.L., Lotz, T., and Brin, B. Mortality among California Seventh-Day Adventists for selected cancer sites. J Natl Cancer Inst. 1980; 65: 1097–1107 PubMed | Google Scholar See all References ] [10] . Northern and central Europe have a higher incidence of pancreatic cancers compared to southern Europe, while in the United States immigrant populations (Scandinavian, eastern European, and Japanese) living in urban areas have higher incidence rates compared with native populations [ 8 x [8] Boyle, P., Hsieh, C.C., Maisonneuve, P., La Vecchia, C., Macfarlane, G.J., and Walker, A.M. Epidemiology of pancreas cancer 1988. Int J Pancreatol. 1989; 5: 327–346 Crossref | PubMed | Scopus (108) | Google Scholar See all References , 11 x [11] Ghadirian, P., Lynch, H.T., and Krewski, D. Epidemiology of pancreatic cancer: an overview. Cancer Detect Prev. 2003; 27: 87–93 Abstract | Full Text | Full Text PDF | PubMed | Scopus (122) | Google Scholar See all References ]. A recent study from England and Wales suggests that the incidence, as well as mortality, for pancreatic cancer perhaps fell over the period 1951–2000. This was particularly pertinent for the male population towards the end of the last century (1996–2000). We investigated whether similar trends could be seen across the world.