Tumor-infiltrating Regulatory T cells – Phenotype and Expansion by Radiation Therapy

Regulatory T cells (Treg) are the master immune-suppressor cells, with a double-edged sword. Treg protect us from autoimmunity, damages from excessive inflammation, and help us maintaining homeostasis in mucosal surface. On the other hand, Treg can be negative force against anti-tumor immunity in the tumor microenvironment (TME), which need to be targeted to maximize the effects of cancer immunotherapies. However, the exact phenotype and molecular basis of suppressive function of Treg in the TME have not been fully elucidated. Especially of translational relevance; what is the phenotype of tumor-infiltrating Treg (TIL-Treg) under the fundamental cancer therapy such as radiotherapy, and what is the determinant molecules for human TIL-Treg have not been fully elucidated. To answer those questions, in my thesis projects, I have elucidated the TIL-Treg phenotype post radiotherapy (RT), and discovered novel human TIL-Treg targeting molecules. In RT-Treg project, we have shown that RT significantly increased the phenotypically activated and, importantly functionally suppressive Treg in the TME. To the best of our knowledge, we were the first to demonstrate that irradiated TIL-Treg are indeed functionally suppressive, using the in vitro micro-suppression assay, using TIL post-RT. Our results also suggest that post-RT Treg expansion is likely independent of TGF-beta nor IL-33, but at least partly due to the proliferation of the Treg in the tumor. In human TIL-Treg project, we performed RNAseq from prostate cancer, glioblastoma and renal cell carcinoma (and urothelial carcinoma as well) patients and identified novel targets highly expressed in TIL-Treg, including DUSP1, DUSP4, RGS1 (and RGS16). Despite its high expression in Treg, DUSP1 showed unique downregulation upon activation, which presents a stark contrast with most Treg-associated molecules many of which increase their expression in activation. DUSP1 accordingly showed reciprocal expression pattern with DUSP4. From the data and close homology with DUSP1 and DUSP4, I hypothesized that DUSP1 and DUSP4 reciprocally regulate Treg activation and function. In depth in vitro and in vivo studies are underway to further elucidate the functional roles of these molecules in TIL-Treg (and TIL)

Tumor-infiltrating Regulatory T cells – Phenotype and Expansion by Radiation Therapy

Regulatory T cells (Treg) are the master immune-suppressor cells, with a double-edged sword. Treg protect us from autoimmunity, damages from excessive inflammation, and help us maintaining homeostasis in mucosal surface. On the other hand, Treg can be negative force against anti-tumor immunity in the tumor microenvironment (TME), which need to be targeted to maximize the effects of cancer immunotherapies. However, the exact phenotype and molecular basis of suppressive function of Treg in the TME have not been fully elucidated. Especially of translational relevance; what is the phenotype of tumor-infiltrating Treg (TIL-Treg) under the fundamental cancer therapy such as radiotherapy, and what is the determinant molecules for human TIL-Treg have not been fully elucidated. To answer those questions, in my thesis projects, I have elucidated the TIL-Treg phenotype post radiotherapy (RT), and discovered novel human TIL-Treg targeting molecules. In RT-Treg project, we have shown that RT significantly increased the phenotypically activated and, importantly functionally suppressive Treg in the TME. To the best of our knowledge, we were the first to demonstrate that irradiated TIL-Treg are indeed functionally suppressive, using the in vitro micro-suppression assay, using TIL post-RT. Our results also suggest that post-RT Treg expansion is likely independent of TGF-beta nor IL-33, but at least partly due to the proliferation of the Treg in the tumor. In human TIL-Treg project, we performed RNAseq from prostate cancer, glioblastoma and renal cell carcinoma (and urothelial carcinoma as well) patients and identified novel targets highly expressed in TIL-Treg, including DUSP1, DUSP4, RGS1 (and RGS16). Despite its high expression in Treg, DUSP1 showed unique downregulation upon activation, which presents a stark contrast with most Treg-associated molecules many of which increase their expression in activation. DUSP1 accordingly showed reciprocal expression pattern with DUSP4. From the data and close homology with DUSP1 and DUSP4, I hypothesized that DUSP1 and DUSP4 reciprocally regulate Treg activation and function. In depth in vitro and in vivo studies are underway to further elucidate the functional roles of these molecules in TIL-Treg (and TIL)

Degradation Analysis of Solid Oxide Fuel Cells with (La,Sr)(Co,Fe)O3-δ Cathode/Gd2O3–CeO2 Interlayer/Y2O3–ZrO2 Electrolyte System: The Influences of Microstructural Change and Solid Solution Formation

Solid oxide fuel cells with a configuration of (La, Sr)(Co, Fe)O3‒δ cathode/doped ceria interlayer/zirconia-based electrolyte have been extensively studied to elucidate the degradation mechanism. Various degradation factors were suggested, such as the formation of highly-resistive SrZrO3 phase, and the reduction in active reaction sites because of the agglomeration of constituent materials. Among them, however, the influence of the ceria-zirconia solid solution formation at the doped ceria interlayer/zirconia-based electrolyte on the cell performance has not been elucidated sufficiently. In this study to achieve a comprehensive understanding of degradation phenomena at the cathode side, the chemical information of constituent materials, as well as the microstructural parameters, were analyzed for single cells before and after discharge operation. Especially, the ionic conductivity of solid solutions formed in the (La, Sr)(Co, Fe)O3‒δ/Gd2O3-CeO2/Y2O3-ZrO2 system was investigated in detail to clarify the ionic conductivity profile at the Gd2O3-CeO2/Y2O3-ZrO2 interface

ExcLAMation marks in a pelvic lymph node

Key Clinical Message Extrapulmonary lymphangioleiomyomatosis (LAM) can present as incidental nodal LAM in gynecological surgery specimens, that warrants systemic investigation and follow‐up of concurrent and subsequent development of pulmonary and extrapulmonary LAM

Inhibitory signaling sustains a distinct early memory CD8 + T cell precursor that is resistant to DNA damage

International audienceThe developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8 + T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1 + pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8 + T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62L hi TCF-1 + subset and subsequent CD8 + T cell memory. Although central memory phenotype CD8 + T cells were formed in the absence of these cells, subsequent memory CD8 + T cell recall responses were compromised. Together, these results identify an impor tant link between genome integrity maintenance and CD8 + T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8 + T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8 + T cell precursor pool may help reconcile models of the developmental origin of long-term CD8 + T cell memory

Hyperprogressive disease during atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma from Japanese real-world practice

Abstract Background Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. Methods Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. Results A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. Conclusion The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated