Lymph Node Stromal Cell Subsets

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRb, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different fromCXCL12highLepRhigh FSCs in themedullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN

A Distinct Subset of Fibroblastic Stromal Cells Constitutes the Cortex-Medulla Boundary Subcompartment of the Lymph Node

The spatiotemporal regulation of immune responses in the lymph node (LN) depends on its sophisticated tissue architecture, consisting of several subcompartments supported by distinct fibroblastic stromal cells (FSCs). However, the intricate details of stromal structures and associated FSC subsets are not fully understood. Using several gene reporter mice, we sought to discover unrecognized stromal structures and FSCs in the LN. The four previously identified FSC subsets in the cortex are clearly distinguished by the expression pattern of reporters including PDGFRβ, CCL21-ser, and CXCL12. Herein, we identified a unique FSC subset expressing both CCL21-ser and CXCL12 in the deep cortex periphery (DCP) that is characterized by preferential B cell localization. This subset was clearly different from CXCL12highLepRhigh FSCs in the medullary cord, which harbors plasma cells. B cell localization in the DCP was controlled chiefly by CCL21-ser and, to a lesser extent, CXCL12. Moreover, the optimal development of the DCP as well as medulla requires B cells. Together, our findings suggest the presence of a unique microenvironment in the cortex-medulla boundary and offer an advanced view of the multi-layered stromal framework constructed by distinct FSC subsets in the LN

Dose-Volume Histogram Analysis in Point A-based Dose Prescription of High-dose-rate Brachytherapy for Cervical Carcinoma

Traditionally, cervical brachytherapy has been prescribed to point A. However, since the Groupe Europ?en de Curieth?rapie and European Society for Radiotherapy＆ Oncology guidelines were published, image-guided brachytherapy has become an emerging technique. The purpose of this study was to evaluate the high-risk clinical target volume （HR-CTV） coverage and analyze dose-volume histograms for organs at risk in point A prescription of high-dose-rate brachytherapy. A total of 68 patients with locally advanced cervical cancer were treated with three-dimensional conformal external beam radiation therapy and brachytherapy from December 2012 to March 2017. Fractions of 6Gy for a total of 12-24Gy were delivered at point A by brachytherapy to all patients. Following each brachytherapy application, a pelvic computed tomography scan was performed and imported into a three-dimensional brachytherapy treatment planning system. In this study, the HR-CTV, bladder, and rectum were re-delineated according to Report 89 of the International Commission on Radiation Units and Measurements using the magnetic resonance images at the time of diagnosis, and the dose-volume histogram of each structure was analyzed. The median age of patients at diagnosis was 67 years （range, 31-91 years）. Mean HR-CTV D90 for all patients was 558.3cGy （range, 228.7-1005.1cGy） and the mean HR-CTV D90 within each clinical T stage was: Ib, 646.4cGy; 2a, 579.3cGy; 2b, 545.2cGy; 3a, 556.6cGy; 3b, 451.3cGy; and 4, 497.9cGy. HR-CTVD90 was correlated with HR-CTV. The mean D2cm3 was 678.1cGy for the bladder and 511.9cGy for the rectum. Using point A-based dose prescription, HR-CTV coverage was insufficient, especially in cases with a large tumor volume or a high T stage. Image-guided brachytherapy is expected to improve HR-CTV coverage while keeping rectal and bladder doses within acceptable levels

Endogenous CCL21-Ser deficiency reduces B16–F10 melanoma growth by enhanced antitumor immunity

The chemokine CCL21 regulates immune and cancer cell migration through its receptor CCR7. The Ccl21a gene encodes the isoform CCL21-Ser, predominantly expressed in the thymic medulla and the secondary lymphoid tissues. This study examined the roles of CCL21-Ser in the antitumor immune response in Ccl21a-knockout (KO) mice. The Ccl21a-KO mice showed significantly decreased growth of B16–F10 and YUMM1.7 melanomas and increased growth of MC38 colon cancer, despite no significant difference in LLC lung cancer and EO771 breast cancer. The B16–F10 tumor in Ccl21a-KO mice showed melanoma-specific activated CD8+ T cell and NK cell infiltration and higher Treg counts than wild-type mice. B16–F10 tumors in Ccl21a-KO mice showed a reduction in the positive correlation between the ratio of regulatory T cells (Tregs) to activated CD8+ T cells and tumor weight. In Ccl21a-KO tumor, the intratumoral Tregs showed lower co-inhibitory receptors TIM-3 and TIGIT. Taken together, these results suggest that endogenous CCL21-Ser supports melanoma growth in vivo by maintaining Treg function and suppressing antitumor immunity by CD8+ T cells