Triple negative breast cancer (TNBC) is a subtype with heterogeneous patient outcomes. Approximately forty percent of patients experience rapid relapse, while the remaining patients have long-term disease-free survival. To determine if there are molecular differences between primary tumors that predict prognosis we performed RNA-seq on 47 macro-dissected tumors from newly diagnosed patients with TNBC (n = 47; 22 relapse, 25 no relapse; follow-up median 8 years, range 2–11 years). We discovered that expression of the MHC class II (MHC II) antigen presentation pathway in tumor tissue was the most significant pathway associated with progression-free survival (hazard ratio (HR) = 0.36, log-rank P = 0.0098). The association between MHC II pathway expression and good prognosis was confirmed in a public gene expression database of 199 TNBC cases (HR = 0.28, log-rank P = 4.5 × 10−8). Further analysis of immunohistochemistry, laser-capture micro-dissected tumors, and TNBC cell lines demonstrated that tumor cells, in addition to immune cells, aberrantly express the MHC II pathway. MHC II pathway expression was also associated with B cell and T cell infiltration in the tumor. Together these data support the model that aberrant expression of the MHC II pathway in TNBC tumor cells may trigger an antitumor immune response that reduces the rate of relapse and enhances progression-free survival.
Growing evidence suggests that plant secondary compounds (PSCs) ingested by mammals become more toxic at elevated ambient temperatures, a phenomenon known as temperature-dependent toxicity. We investigated temperaturedependent toxicity in the desert woodrat (Neotoma lepida), a herbivorous rodent that naturally encounters PSCs in creosote bush (Larrea tridentata), which is a major component of its diet. First, we determined the maximum dose of creosote resin ingested by woodrats at warm (28-298C) or cool (21-228C) temperatures. Second, we controlled the daily dose of creosote resin ingested at warm, cool and room (258C) temperatures, and measured persistence in feeding trials. At the warm temperature, woodrats ingested significantly less creosote resin; their maximum dose was two-thirds that of animals at the cool temperature. Moreover, woodrats at warm and room temperatures could not persist on the same dose of creosote resin as woodrats at the cool temperature. Our findings demonstrate that warmer temperatures reduce PSC intake and tolerance in herbivorous rodents, highlighting the potentially adverse consequences of temperature-dependent toxicity. These results will advance the field of herbivore ecology and may hone predictions of mammalian responses to climate change.
<p>This file contains: Supplementary Methods for Tissue Processing, RNA-seq, RNA-seq analysis, and Immunohistochemistry. Supplementary Figure 1: Overlap between clusters identified in our data and TNBC subtypes described in previous studies. Supplementary Figure 2: Heatmap of the normalized gene expression values of each of the 24 prognostic genes in each of the 47 patient's tumors. Supplementary Figure 3: Illustration of TNBC prognostic genes in the MHC II pathway. Supplementary Figure 4: Kaplan-Meier PFS curves of patients with expression levels (tertiles) of CIITA and CD74. Supplementary Table 1: Gene Expression Cluster Content and Outcomes Supplementary Table 2: Correlation Coefficient and Hazard Ratio of MHCII Genes</p>
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