Biological Aging Marker p16INK4a in T Cells and Breast Cancer Risk

Prior research has demonstrated that altered telomere length, a well-known marker for biological aging, is associated with various types of human cancer. However, whether such association extends to additional hallmarks of biological aging, including cellular senescence, has not been determined yet. In this two-stage study, we assessed the association between p16INK4a mRNA expression in T cells, a marker of cellular senescence, and breast cancer risk. The discovery stage included 352 breast cancer patients and 324 healthy controls. p16INK4a mRNA expression was significantly higher in individuals who were older, Black, and had family history of cancer than their counterparts in both cases and controls. p16INK4a mRNA expression also differed by marital status, annual income, and smoking status in cases. In the discovery stage, we found that increased p16INK4a mRNA expression was associated with 1.40-fold increased risk of breast cancer (OR = 1.40; 95%CI: 1.21, 1.68; p < 0.001). A marginally significant association was further observed in the validation stage with 47 cases and 48 controls using pre-diagnostic samples (OR = 1.28; 95%CI: 0.98, 2.97; p = 0.053). In addition, we found that p16INK4a mRNA expression was higher in tumors with selected aggressive characteristics (e.g., poorly differentiated and large tumors) than their counterparts. In summary, our results demonstrate that higher p16INK4a mRNA expression in T cells is a risk factor for breast cancer and further support the role of biological aging in the etiology of breast cancer development. Novelty and Impact Statements: The results from this study provide evidence that cellular senescence, a process of biological aging, plays a role in breast cancer etiology. In addition, our results also support that social demographics may modify cellular senescence and biological aging

Correction: Shen, J.; et al. Biological Aging Marker p16INK4a in T Cells and Breast Cancer Risk. Cancers 2020, 12, 3122

The authors wish to make the following corrections to this paper [...

Atomic controllable anchoring of uranium into zirconate pyrochlore with ultrahigh loading capacity

Efficient immobilization of actinide wastes is challenging in the nuclear energy industry. Here, we reported that 100% substitution of Zr$^{4+}$ by U$^{6+}$ in a La$_{2}$Zr$_{2}$O$_{7}$ matrix has been achieved for the first time by the molten salt (MS) method. Importantly, we observed that uranium can be precisely anchored into Zr or La sites of the La$_{2}$Zr$_{2}$O$_{7}$ matrix, as confirmed by X-ray diffraction, Raman, and X-ray absorption spectra. This work will guide the construction of site-controlled and high-capacity actinide-immobilized pyrochlore materials and could be extended to other perovskite materials

A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin

Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. Methods: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). Results: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. Conclusion: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death

A Case Study of Chimeric Antigen Receptor T Cell Function: Donor Therapeutic Differences in Activity and Modulation with Verteporfin

Background: Chimeric antigen receptor (CAR) T cells have recently been demonstrated to extract and express cognate tumor antigens through trogocytosis. This process may contribute to tumor antigen escape, T cell exhaustion, and fratricide, which plays a central role in CAR dysfunction. We sought to evaluate the importance of this effect in epidermal growth factor receptor variant III (EGFRvIII) specific CAR T cells targeting glioma. Methods: EGFRvIII-specific CAR T cells were generated from various donors and analyzed for cytotoxicity, trogocytosis, and in vivo therapeutic activity against intracranial glioma. Tumor autophagy resulting from CAR T cell activity was evaluated in combination with an autophagy inducer (verteporfin) or inhibitor (bafilomycin A1). Results: CAR T cell products derived from different donors induced markedly divergent levels of trogocytosis of tumor antigen as well as PD-L1 upon engaging target tumor cells correlating with variability in efficacy in mice. Pharmacological facilitation of CAR induced-autophagy with verteporfin inhibits trogocytic expression of tumor antigen on CARs and increases CAR persistence and efficacy in mice. Conclusion: These data propose CAR-induced autophagy as a mechanism counteracting CAR-induced trogocytosis and provide a new strategy to innovate high-performance CARs through pharmacological facilitation of T cell-induced tumor death