Cancer cells expressing PD-1 ligands (PD-L1/PD-L2) inhibit immune-modulatory T-cell activation facilitating disease progression. Preliminary clinical trials exploring interruption of PD-1/PD-L1 signaling showed benefit in several cancer types. We analyzed the distribution of PD-1-positive tumor-infiltrating lymphocytes (TIL) and cancer cells' expression of PD-L1 in a molecularly profiled cohort of 437 malignancies (380 carcinomas, 33 sarcomas, and 24 melanomas). We showed that the presence of PD-1 þ TILs significantly varied among cancer types (from 0% in extraskeletal myxoid chondrosarcomas to 93% in ovarian cancer), and was generally associated with the increased number of mutations in tumor cells (P ¼ 0.029). Cancer cell expression of PD-L1 varied from absent (in Merkel cell carcinomas) to 100% (in chondro-and liposarcomas), but showed the inverse association with the number of detected mutations (P ¼ 0.004). Both PD-1 and PD-L1 expression were significantly higher in triple-negative breast cancers (TNBC) than in non-TNBC (P < 0.001 and 0.017, respectively). Similarly, MSI-H colon cancers had higher PD-1 and PD-L1 expression than the microsatellite stable tumors (P ¼ 0.002 and 0.02, respectively). TP53-mutated breast cancers had significantly higher PD-1 positivity than those harboring other driver mutations (e.g., PIK3CA; P ¼ 0.002). In non-small cell lung cancer, PD-1/PD-L1 coexpression was identified in 8 cases (19%), which lacked any other targetable alterations (e.g., EGFR, ALK, or ROS1). Our study demonstrated the utility of exploring the expression of two potentially targetable immune checkpoint proteins (PD-1/PD-L1) in a substantial proportion of solid tumors, including some aggressive subtypes that lack other targeted treatment modalities. Cancer Epidemiol Biomarkers Prev; 23(12); 2965-70. Ó2014 AACR.

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Experimental animal models of cancer have provided invaluable information about the mechanisms of tumor development, progression and metastasis. Despite the high prevalence of prostate cancer and the burden of disease on society, few laboratory and preclinical models of prostate cancer have been developed that approximate the spectrum of tumor progression and metastatic disease. Notwithstanding improvements in the diagnosis and treatment of localized prostate cancer in recent years, metastatic disease presents a formidable challenge and is lethal for men with advanced prostate cancer. 1 This has spurred efforts to understand the mechanisms responsible for the switch from the indolent to the metastatic tumor phenotype. 2 Elucidation of the molecular pathways that regulate metastasis depends on the availability of clinically relevant in vivo animal models of prostate cancer that serve as laboratory surrogates to assess the efficacy of therapeutic or preventive modalities in vivo.Xenograft models of prostate cancer that mimic features of the human disease have been developed in immunodeficient mice. 3 These models have been critical in the identification of genes involved in tumor growth and progression and are employed extensively for testing novel drug, irradiation and emerging gene therapies. Moreover, orthotopic implantation of prostate tumor cells or tissue in nude mice resulted in the derivation of sublines with the capacity for enhanced tumor take and increased lymph node and distant metastasis. 4 -7 Transgenic and reconstitution models of prostate cancer have been used to study prostate carcinogenesis, metastasis, and to test novel therapeutic and chemoprevention regimens. 8,9 The mouse prostate reconstitution (MPR) model utilizes fetal mouse urogenital sinus tissue that is infected ex vivo with recombinant retroviruses then implanted into mice. 9 Transgenic mouse models of prostate cancer have been developed in which the rat probasin promoter targets prostate epithelial cell-specific expression of SV40 T antigen (Tag) leading to the development of spontaneous autochthonous prostate cancer that is regulated temporally and spatially. 10,11 In the transgenic adenocarcinoma mouse prostate (TRAMP) model, all males develop primary prostate tumors and metastases to distant sites between 18 -24 weeks of age. 12 We demonstrated previously that treatment of mice bearing ectopic transplantable TRAMP-C1 tumors with flt3 ligand (L), a hematopoietic growth factor, resulted in transient tumor regression without long-term antitumor immunity. 13 We describe the establishment of an orthotopic model of primary prostate cancer and lymph node metastasis in immunocompetent mice. To establish the use of this model for immunotherapy, the therapeutic efficacy of flt3L was assessed in mice with orthotopic, metastatic prostate cancer. MATERIAL AND METHODS Cell lines and cultureThe parental transplantable epithelial prostate cancer cell line, TRAMP-C1, derived from a prostate adenocarcinoma in transAbbreviations: TRAMP, transgenic a...

Flow cytometric DNA ploidy analysis has been reported to be more objective and sensitive than morphologic evaluation as a surveillance method in patients with Barrett esophagus (BE) for the development and progression of precancerous lesions. Such analyses are typically performed using fresh samples that require a separate or "jumbo" biopsy, are prone to false DNA aneuploidy if not promptly processed, and do not allow for retrospective studies. The feasibility of performing flow cytometric DNA analysis on paraffin-embedded biopsies was studied to circumvent some of these problems using 12 squamous esophageal mucosa with inflammation and 58 BE cases showing varying degrees of dysplasia. Among the BE cases, 12 had no dysplasia, 20 were indefinite for dysplasia, 14 had low grade dysplasia, and 12 had high grade dysplasia. Satisfactory histograms were obtained in 86% of the analyzed An increased risk ofdeveloping carcinoma has been well established among patients with ulcerative colitis (UC) and Barrett esophagus (BE). It has become standard medical practice to perform periodic surveillance endoscopy with biopsy for the detection of dysplasia, a presumed precancerous lesion. Because consistent and objective detection of precancerous changes by histology may not be always possible, other adjunctive methods that are more objective and/or sensitive have been explored, including flow cytometric DNA ploidy analysis. The latter has been performed using fresh mucosal samples in the vast majority of reported studies.1 " 4 We recently reported the technical feasibility and advantages of using formalin-fixed and paraffin-embedded mucosal biopsy samples in patients with UC.5 Herein, we have analyzed DNA ploidy by flow cytometry using archival paraffin-embedded mucosal biopsies from patients with BE and dysplasia. MATERIALS AND METHODS Case SelectionA total of 58 BE cases with varying degree of dysplasia accessioned between 1990 and 1995 were retrieved from the files of the Armed Forces Institute of Pathology and Georgetown University. All hematoxylin-and-eosinstained slides were reviewed by two of the authors (EAM, NJC) using established criteria for dysplasia in BE. 6 The diagnosis of "indefinite" for dysplasia was assigned when moderate nuclear atypia was associated with active inflammation or only minimal nuclear abnormalities were present. A group of control cases (12 cases) showing inflamed esophageal squamous epithelium were selected from files of Georgetown University. In all cases, formalin-fixed and paraffin-embedded tissue blocks were available. DNA AnalysisParaffin blocks from these cases were processed for flow cytometry using the modified Hedley technique, 78 2 9 8