Yifan Chen

Objective Our previous studies have identified CXCL8 as the crucial chemokine responsible for gastric cancer metastasis mediated by loss of RACK1. However, the regulatory effect of CXCL8 on immune surveillance in gastric cancer remains obscure. Design Flow cytometry analyses were performed to examine major source of CXCL8 and phenotypes of immune cells in fresh tumour tissues from 76 patients with gastric cancer. Real-time PCR was performed to analyse CXCL8 mRNA level in gastric cancer tissues. For immunohistochemical analyses, a total of 420 patients with gastric cancer undergoing curative resection were enrolled. In vitro culture of fresh tumour tissue was performed to evaluate the potential therapeutic effect of blocking CXCL8 pathway in gastric cancer. Results Increased level of CXCL8 indicates poor clinical outcome and tumour progression in patients with gastric cancer. In gastric cancer tissues, CXCL8 is predominantly secreted by macrophages and colony stimulating factor 2 (CSF-2) facilitates macrophage-derived CXCL8 secretion. High level of CXCL8 is associated with decreased CD8 + T cells infiltration and Ki67 + CD8 + T cells proportion. Moreover, CXCL8 also inhibits CD8 + T cells function by inducing the expression of PD-L1 on macrophages. Finally, we show that a small-molecule CXCR2 inhibitor, reparixin, drives the decreased programmed death-ligand 1 (PD-L1 + ) macrophages and promotes antitumour immunity. Accordingly, high levels of CXCL8 + macrophages are positively correlated with poor prognosis in patients with gastric cancer. Conclusions CXCL8 is predominantly secreted by macrophages and contributes to the immunosuppressive microenvironment by inducing PD-L1 + macrophages in gastric cancer. CXCL8 inhibitors may drive antitumour response, providing potential therapeutic effects for patients with gastric cancer.

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.

Abstract Tumor-associated macrophages (TAM) play an indispensable role in the modulation of the cancer immune microenvironment. Despite the fact that TAMs may exert both antitumor and protumor activities, the molecular mechanisms involved remain poorly understood. Here, we characterized a subpopulation of TAMs expressing dendritic cell–specific C-type lectin (DC-SIGN) and investigated its relevance to the prognosis and immune microenvironment of muscle-invasive bladder cancer (MIBC). DC-SIGN+ TAMs were abundant in a significant proportion of human MIBC specimens. High levels of DC-SIGN+ TAMs were associated with dismal prognosis and unresponsiveness to adjuvant chemotherapy in MIBC. Notably, multiple anti-inflammatory cytokines were enriched in DC-SIGN+ TAMs. RNA-seq analysis revealed that multiple M2-like signaling pathways were significantly upregulated in DC-SIGN+ TAMs. High infiltration of DC-SIGN+ TAMs was associated with CD8+ T-cell tolerance in MIBC. Moreover, abrogating DC-SIGN function using a neutralizing antibody led to impaired expression of anti-inflammatory cytokines and augmented PD-1 inhibitor pembrolizumab-mediated cytotoxic effects of CD8+T cells toward MIBC cells. In summary, these results suggest that DC-SIGN+ TAM infiltration is closely linked to a protumor immune microenvironment and may serve as a promising therapeutic target in the immunotherapy of MIBC. Significance: DC-SIGN+ TAMs have an immunosuppressive and tumor-promoting function and may serve as a prognostic indicator and therapeutic target in MIBC.

In recent years, structural and functional studies reveal that tyrosine kinases (TKs) act as the essential components of signal transduction pathways that regulate cancer cell proliferation, apoptosis and angiogenesis, and therefore become potential targets for anticancer therapy. Most of TK inhibitors (TKIs) are small molecular and hydrophobic compounds, thus they can rapidly reach their specific intracellular targets and inhibit the activation of the related TKs. Unfortunately, accompanied with patients who gain great benefit of TKIs therapy, increasing evidences of acquired resistance to these agents have been documented. The unveiling point mutations within the kinase domain, gene amplification or overexpression, or modification of signaling pathway have been implicated in drug resistance. Additionally, overexpression of ABC transporters is likely to set stage for resistant development. In this review, we focus on the discussion of the molecular mechanisms of acquired resistance to TKIs therapy. The mechanistic understanding may help to put forward new hypotheses on drug development and design better therapies to overcome TKIs resistance.