Uveal melanoma (UM) is a highly metastatic cancer that, in contrast to cutaneous melanoma, is largely unresponsive to checkpoint immunotherapy. Here, we interrogate the tumor microenvironment at single-cell resolution using scRNA-seq of 59,915 tumor and nonneoplastic cells from 8 primary and 3 metastatic samples. Tumor cells reveal novel subclonal genomic complexity and transcriptional states. Tumor-infiltrating immune cells comprise a previously unrecognized diversity of cell types, including CD8 + T cells predominantly expressing the checkpoint marker LAG3, rather than PD1 or CTLA4. V(D)J analysis shows clonally expanded T cells, indicating that they are capable of mounting an immune response. An indolent liver metastasis from a class 1B UM is infiltrated with clonally expanded plasma cells, indicative of antibody-mediated immunity. This complex ecosystem of tumor and immune cells provides new insights into UM biology, and LAG3 is identified as a potential candidate for immune checkpoint blockade in patients with high risk UM.

BACKGROUND.Differences in cancer survival based on race, ethnicity, and socioeconomic status (SES) are a major issue. To identify points of intervention and improve survival, the authors sought to determine the impact of race, ethnicity, and socioeconomic status for patients with cancers of the head and neck (HN).METHODS.HN cancer patients diagnosed between 1998 and 2002 were examined using a linked Florida Cancer Data System and Florida Agency for Health Care Administration data set.RESULTS.A total of 20,915 patients with HN cancers were identified, predominantly in the oral cavity and larynx. Overall, 72% of patients were male, 89.7% were white, 8.4% were African American (AA), and 10.6% were Hispanic. The median survival time (MST) was 37 months. MST varied significantly by race (white, 40 months vs AA, 21 months; P < .001), sex (men, 36 months vs women, 41 months; P = .001), and area poverty level (lowest, 27 months vs highest, 34 months; P < .0001). Only 32% of AA patients underwent surgery in comparison with 45% of white patients (P < .001). On multivariate analysis, independent predictors of poorer outcomes were race, poverty, age, sex, tumor site, stage, grade, treatment modality, and a history of smoking and alcohol consumption.CONCLUSIONS.Carcinomas of the HN have an overall high mortality with a disproportionate impact on AA patients and the poor. Dramatic disparities by race and SES are not explained completely by demographics, comorbid conditions, or undertreatment. Earlier diagnosis and greater access to surgery and adjuvant therapies in these patients would likely yield significant improvement in outcomes. Cancer 2008. © 2008 American Cancer Society.

: STS patients treated at HVC have significantly better survival and functional outcomes. Patients with either large (>10 cm), high-grade or truncal/retroperitoneal tumors should be treated exclusively at a high-volume center.

BRCA1 mutation carriers are predisposed to developing basal-like breast cancers with high metastasis and poor prognosis. Yet, how BRCA1 suppresses formation of basal-like breast cancers is still obscure. Deletion of p18 Ink4c (p18), an inhibitor of CDK4 and CDK6, functionally inactivates the RB pathway, stimulates mammary luminal stem cell (LSC) proliferation, and leads to spontaneous luminal tumor development. Alternately, germline mutation of Brca1 shifts the fate of luminal cells to cause luminal-to-basal mammary tumor transformation. Here, we report that disrupting Brca1 by either germline or epithelium-specific mutation in p18-deficient mice activates epithelial-to-mesenchymal transition (EMT) and induces dedifferentiation of LSCs, which associate closely with expansion of basal and cancer stem cells and formation of basal-like tumors. Mechanistically, BRCA1 bound to the TWIST promoter, suppressing its activity and inhibiting EMT in mammary tumor cells. In human luminal cancer cells, BRCA1 silencing was sufficient to activate TWIST and EMT and increase tumor formation. In parallel, TWIST expression and EMT features correlated inversely with BRCA1 expression in human breast cancers. Together, our findings showed that BRCA1 suppressed TWIST and EMT, inhibited LSC dedifferentiation, and repressed expansion of basal stem cells and basal-like tumors. Thus, our work offers the first genetic evidence that Brca1 directly suppresses EMT and LSC dedifferentiation during breast tumorigenesis. Cancer Res; 74(21); 6161-72. Ó2014 AACR.