Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL.

Leiomyosarcoma (LMS) is the most common uterine sarcoma. Although the disease is relatively rare, it is responsible for considerable mortality due to frequent metastasis and chemoresistance. The molecular events related to LMS metastasis are unknown to date. The present study compared the global gene expression patterns of primary uterine LMS and LMS metastases. Gene expression profiles of 13 primary and 15 metastatic uterine LMS were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time PCR and immunohistochemistry. To identify differently expressed genes between primary and metastatic tumors, we performed one-way ANOVA with Benjamini-Hochberg correction. This lead to identification of 203 unique probes that were significantly differentially expressed in the two tumor groups by greater than 1.58-fold with p-value <0.01%, of which 94 and 109 were overexpressed in primary and metastatic LMS, respectively. Genes overexpressed in primary uterine LMS included OSTN, NLGN4X, NLGN1, SLITRK4, MASP1, XRN2, ASS1, RORB, HRASLS and TSPAN7. Genes overexpressed in LMS metastases included TNNT1, FOLR3, TDO2, CRYM, GJA1, TSPAN10, THBS1, SGK1, SHMT1, EGR2 and AGT. Quantitative real-time PCR confirmed significant anatomic site-related differences in FOLR3, OSTN and NLGN4X levels, and immunohistochemistry showed significant differences in TDO2 expression. Gene expression profiling differentiates primary uterine LMS from LMS metastases. The molecular signatures unique to primary and metastatic LMS may aid in understanding tumor progression in this cancer and in providing a molecular basis for prognostic studies and therapeutic target discovery.

Hormone receptor expression is not informative of outcome in the analysis of uterine sarcomas of all stages and histologic types. PR expression identifies patients with longer survival in stage I leiomyosarcoma.

No abstract

We analyzed the expression and clinical role of endoglin (CD105) in breast carcinoma effusions. Endoglin levels were measured in 36 effusion supernatants by ELISA and studied for association with the cancer-associated markers calprotectin, VEGF, and the VEGF receptor sFlt1. Endoglin expression was further studied in 46 effusions and 22 primary carcinomas using immunohistochemistry. The four secreted molecules were detected in all specimens and their levels significantly correlated (p < 0.001). In effusions, endoglin was localized to carcinoma cells and reactive mesothelium using immunohistochemistry. Tumor cell expression was higher in effusions compared to primary carcinomas (p = 0.025), and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.017). Higher tumor endoglin expression was associated with poor overall (p = 0.021) and disease-free (p = 0.032) survival in univariate analysis, and was an independent predictor in Cox multivariate analysis (p = 0.001 and p = 0.038, respectively). Our data suggest that endoglin may be an important therapeutic target in metastatic breast cancer.