HSF1 Inhibits Antitumor Immune Activity in Breast Cancer by Suppressing CCL5 to Block CD8+ T-cell Recruitment.

Heat shock factor 1 (HSF1) is a stress-responsive transcription factor that promotes cancer cell malignancy. To provide a better understanding of the biological processes regulated by HSF1, here we developed an HSF1 activity signature (HAS) and found that it was negatively associated with antitumor immune cells in breast tumors. Knockdown of HSF1 decreased breast tumor size and caused an influx of several antitumor immune cells, most notably CD8+ T cells. Depletion of CD8+ T cells rescued the reduction in growth of HSF1-deficient tumors, suggesting HSF1 prevents CD8+ T-cell influx to avoid immune-mediated tumor killing. HSF1 suppressed expression of CCL5, a chemokine for CD8+ T cells, and upregulation of CCL5 upon HSF1 loss significantly contributed to the recruitment of CD8+ T cells. These findings indicate that HSF1 suppresses antitumor immune activity by reducing CCL5 to limit CD8+ T-cell homing to breast tumors and prevent immune-mediated destruction, which has implications for the lack of success of immune modulatory therapies in breast cancer. SIGNIFICANCE: The stress-responsive transcription factor HSF1 reduces CD8+ T-cell infiltration in breast tumors to prevent immune-mediated killing, indicating that cellular stress responses affect tumor-immune interactions and that targeting HSF1 could improve immunotherapies.

CT texture analysis in the differentiation of major renal cell carcinoma subtypes and correlation with Fuhrman grade.

OBJECTIVE: CT texture analysis (CTTA) using filtration-histogram-based parameters has been associated with tumor biologic correlates such as glucose metabolism, hypoxia, and tumor angiogenesis. We investigated the utility of these parameters for differentiation of clear cell from papillary renal cancers and prediction of Fuhrman grade. METHODS: A retrospective study was performed by applying CTTA to pretreatment contrast-enhanced CT scans in 290 patients with 298 histopathologically confirmed renal cell cancers of clear cell and papillary types. The largest cross section of the tumor on portal venous phase axial CT was chosen to draw a region of interest. CTTA comprised of an initial filtration step to extract features of different sizes (fine, medium, coarse spatial scales) followed by texture quantification using histogram analysis. RESULTS: A significant increase in entropy with fine and medium spatial filters was demonstrated in clear cell RCC (p = 0.047 and 0.033, respectively). Area under the ROC curve of entropy at fine and medium spatial filters was 0.804 and 0.841, respectively. An increased entropy value at coarse filter correlated with high Fuhrman grade tumors (p = 0.01). The other texture parameters were not found to be useful. CONCLUSION: Entropy, which is a quantitative measure of heterogeneity, is increased in clear cell renal cancers. High entropy is also associated with high-grade renal cancers. This parameter may be considered as a supplementary marker when determining aggressiveness of therapy. KEY POINTS: • CT texture analysis is easy to perform on contrast-enhanced CT. • CT texture analysis may help to separate different types of renal cancers. • CT texture analysis may enhance individualized treatment of renal cancers.