BackgroundChemokine (C-X-C motif) ligand 13 (CXCL13) was known as a selective chemotaxis for B cells, a product of follicular helper CD4+T cells (TFH) and a contributor to tertiary lymphoid structures (TLS). Although secretion and function of CXCL13 produced by TFH 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).MethodsWe 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.ResultsIntratumoral 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.ConclusionsIntratumoral 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.

Objective: To investigate the clinical significance of IL-10 þ tumor-associated macrophages (TAMs) in gastric cancer. Background: Due to the plasticity and diversity of TAMs, it is necessary to phenotypically and functionally classify subsets of TAMs to better understand the critical role of TAMs in cancer progression. TAMs expressing interleukin-10 (IL-10) have been found to facilitate immune evasion in many malignancies, but the role of IL-10 þ TAMs in gastric cancer remains obscure. Methods: Four hundred and sixty-eight tumor tissue microarray specimens, 52 fresh tumor tissue samples of gastric cancer patients from Zhongshan Hospital, and data of 298 gastric cancer patients from the Cancer Genome Atlas (TCGA) were analyzed. IL-10 þ TAM level and immune contexture were examined by CIBERSORT, immunohistochemistry, and flow cytometry. Clinical outcomes were analyzed by Kaplan-Meier curves and Cox model. Results: Gastric cancer patients with high IL-10 þ TAM infiltration exhibited poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. IL-10 þ TAM infiltration yielded an immunoevasive tumor microenvironment featured by regulatory T cell infiltration and CD8 þ T cell dysfunction. The combinational analysis of IL-10 þ TAM and CD8 þ T cell infiltration stratified patients into distinct risk groups with different clinical outcomes. Moreover, IL-10 þ TAM infiltration was correlated with tumor-intrinsic characteristics including EBV status, PD-L1 expression, and genome stability in gastric cancer. Conclusions: This study revealed that IL-10 þ TAMs might drive an immunoevasive microenvironment and determine poor prognosis and inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy,indicating IL-10 þ TAMs could be applied as a potential target for immunotherapeutic approach in gastric cancer.

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BackgroundTumor-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).MethodsIn 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.ResultsHigh 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.ConclusionsImmunosuppresive 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.

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