Zhaopei Liu

Background Chemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4 + T cells (T FH ) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by T FH have been deeply explored, the immune function and prognostic significance of CXCL13 secreted by CD8 + T cells still remain unrevealed. This study aims to investigate the clinical merit of CXCL13 + CD8 + T cells in clear cell renal cell carcinoma (ccRCC). Methods We analyzed prognostic value and immune contexture that associated with CXCL13 + CD8 + T cells infiltration level in a total of 755 patients from Zhongshan Hospital cohort (n=223) and The Cancer Genome Atlas cohort (n=532). In vitro analyses were conducted on 42 samples of resected tumor tissue from Zhongshan Hospital in order to detect the immune status of CXCL13 + CD8 + T cells and total CD8 + T cells. Immunohistochemistry (IHC) and flow cytometry were applied to characterize immune cells and portray the tumor microenvironment (TME) in ccRCC. Results Intratumoral CXCL13 + CD8 + T cells abundance was associated with inferior overall survival and disease-free survival. CXCL13 + CD8 + T cells possessed higher level of immune checkpoints like programmed cell-death protein 1 (PD-1), T-cell immunoglobulin mucin 3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), higher Ki-67 expression and lower tumor necrosis factor α (TNF-α), interferon γ (IFN-γ) expression. Total CD8 + T cells in high-level CXCL13 + CD8 + T cells infiltration subgroup exhibited elevated exhausted markers (PD-1, Tim-3, TIGIT) and descended activated markers (TNF-α, IFN-γ) without quantity variance. Furthermore, the abundance of intratumoral CXCL13 + CD8 + T cell was correlated with immunoevasive TME accompanied by increased T helper 2 cells, tumor-associated macrophages, Foxp3 + regulatory T cells, TLS and decreased natural killer cells, GZMB + cells. Conclusions Intratumoral CXCL13 + CD8 + T cells infiltration indicated inferior clinical outcome in patients with ccRCC. CXCL13 + CD8 + T cells possessed increased exhausted markers, decreased effector molecules and better proliferation ability. CXCL13 + CD8 + T cells abundance impaired total CD8 + T cells’ immune function. Intratumoral CXCL13 + CD8 + T cells abundance was associated with immunoevasive contexture. The abundance of CXCL13 + CD8 + T cells was an independent prognosticator and a potential immunotherapeutic target marker for ccRCC treatment.

Background T-cell immunoglobulin and ITIM domain (TIGIT) is identified as a novel checkpoint receptor that can facilitate immune escape via mediating T-cell exhaustion in tumors. However, the clinical significance and immune contexture correlation of intratumoral TIGIT + CD8 + T-cells remain to be further explored in muscle-invasive bladder cancer (MIBC). Methods 259 patients with MIBC from two clinical centers (Zhongshan Hospital, n=141; Shanghai Cancer Center, n=118) were analyzed to evaluate the prognostic value and immune contexture association of TIGIT + CD8 + T-cells through immunohistochemistry. Fresh tumor tissue samples from 26 patients with MIBC were examined to discover the phenotype of this CD8 subpopulation by flow cytometry. Results High infiltration of intratumoral TIGIT + CD8 + T-cells predicted poor overall survival (OS) and recurrence-free survival (RFS) in MIBC. For patients with stage II MIBC with low infiltration of TIGIT + CD8 + cells, adjuvant chemotherapy (ACT) could significantly prolong their OS and RFS. Intratumoral TIGIT + CD8 + T-cell abundance was correlated with impaired CD8 + T-cell cytotoxicity and exhibited production of immunosuppressive cytokine IL-10. Further analysis of tumor-infiltrating immune cell landscape revealed TIGIT + CD8 + T-cells were associated with suppressive immune contexture, including Th2 cells, regulatory T-cells, mast cells and neutrophils. Conclusion Intratumoral TIGIT + CD8 + T-cell abundance could serve as an independent prognosticator for clinical outcome and a predictive biomarker for inferior ACT responsiveness. Intratumoral TIGIT + CD8 + T-cell abundance correlated with dampened CD8 + T-cell antitumor immunity and immunosuppressive contexture abundance, highlighting a tumor-promoting role of TIGIT + CD8 + T-cells.

Background Tumor-associated macrophages (TAMs) secreting IL-10 could be a specific functional cell subset with distinct polarization state and suppressive role in antitumor immune response. Here, we assessed the associations of clinical outcome, therapeutic responses and molecular features with IL-10 + TAMs infiltration, and potential impact of IL-10 + TAMs on the immune contexture in muscle-invasive bladder cancer (MIBC). Methods In this retrospective study, 128 patients and 391 patients with MIBC from Zhongshan hospital (ZS cohort) and The Cancer Genome Atlas cohort were included respectively. Immunohistochemistry was performed to quantify various immune cell infiltration in the ZS cohort. Single cell RNA sequencing and flow cytometry were performed to examine the functional status of IL-10 + TAMs and its correlation with other immune cells. Survival analyses and assessment of the adjuvant chemotherapy (ACT) benefit analyses were also performed. Results High IL-10 + TAMs infiltration was associated with inferior prognosis in terms of overall survival and recurrence-free survival, but superior chemotherapeutic response in MIBC. IL-10 + TAMs with suppressive features were associated with immunoevasive tumor microenviroment characterized by exhausted CD8 + T cells, immature NK cells and increased immune checkpoint expression. Additionally, high IL-10 + TAMs infiltration showed a strong linkage with basal-featured subtype and augmented EGF signaling. Conclusions Immunosuppresive IL-10 + TAMs contributed to an evasive contexture with incapacitated immune effector cells and increased immune checkpoint expression, therefore, predicting unfavorable clinical outcomes despite better ACT responsiveness. IL-10 + TAMs might provide guidance for customized selection of EGFR-targeted therapy, FGFR3-targeted therapy as well as immunotherapy. The potential of immunosuppressive IL-10 + TAMs as a therapeutic target is worth further exploration.

We theoretically and experimentally study the spin Hall effect of reflected light at an air-uniaxial crystal interface. The spin-dependent nanometer-sized displacements depend not only on the incident polarization and the incident angle of the light beam, but also on the orientation of the crystal optic axis. The experimental results are in perfect agreement with theoretical predictions for the vertical and horizontal polarization incidence.

Background Lymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3 + cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment. Methods 141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8 + T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration. Results In Kaplan-Meier analyses and Cox regression models, stromal LAG-3 + cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3 + cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8 + T cells correlated its dysfunctional state with LAG-3 + cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway. Conclusions Stromal LAG-3 + cells abundance indicated an immunoevasive contexture with dysfunctional CD8 + T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3 + cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.