Studies have reported a positive correlation between elevated CD8+ T cells in the tumor microenvironment (TME) and good prognosis in cancer. However, the mechanisms linking T cell tumor-infiltration and tumor rejection are yet to be fully understood. The cells and factors of the TME facilitate tumor development in various ways. CD8+ T cell function is influenced by a number of factors, including CD8+ T cell trafficking and localization into tumor sites; as well as CD8+ T cell growth and differentiation. This review highlights recent literature as well as currently evolving concepts regarding the fates of CD8+ T cells in the TME from three different aspects CD8+ T cell trafficking, differentiation and function. A thorough understanding of factors contributing to the fates of CD8+ T cells will allow researchers to develop new strategies and improve on already existing strategies to facilitate CD8+ T cell mediated anti-tumor function, impede T cell dysfunction and modulate the TME into a less immunosuppressive TME.

BackgroundChemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function.MethodsWe determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-γ, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8+ T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites.ResultsWe found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8+ T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-κB activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients.ConclusionsOur results demonstrate that DOC induces CD8+ T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0511-6) contains supplementary material, which is available to authorized users.

IFNg is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFNg in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFNg can induce cancer progression, yet the mechanisms underlying the controversial role of IFNg in tumor development remain unclear. Here, we reveal a dose-dependent effect of IFNg in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFNg endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of IFNg activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stemlike properties of NSCLC cells induced by the low dose of IFNg both in vitro and in vivo. This study unveils the role of low levels of IFNg in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFNg in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFNg in the TME. Significance: These findings reveal the dose-dependent effect of IFNg in inducing tumor stemness and elucidate the distinct molecular mechanisms activated by IFNg in a dosedependent manner.

Metformin has been studied for its anticancer effects by regulating T cell functions. However, the mechanisms through which metformin stimulates the differentiation of memory T cells remain unclear. We found that the frequencies of memory stem and central memory T cells increased for both in peripheral and tumor-infiltrating CD8+ T cells in metformin-treated lung cancer patients compared with those not taking the medication. An in vitro assay showed that metformin promoted the formation of memory CD8+ T cells and enhanced their antiapoptotic abilities. In addition, AMP-activated protein kinase (AMPK) activation decreased microRNA-107 expression, thus enhancing Eomesodermin expression, which suppressed the transcription of PDCD1 in metformin-treated CD8+ T cells. In the CAR-T cell therapy model, metformin also exhibited cytotoxicity-promoting effects that led to decreased tumor growth. Metformin could reprogram the differentiation of CD8+ T cells, which may benefit the clinical therapy of cancer patients by facilitating long-lasting cytotoxic functions.

The expression and function of CD163 in glioma are not fully understood. In this report, we collected totally 1323 glioma samples from the Chinese Glioma Genome Atlas (CGGA) dataset, including 325 RNA-seq data and 301 mRNA microarray data, and 697 glioma samples from The Cancer Genome Atlas (TCGA) dataset to characterize the molecular and clinical features of CD163 in glioma by conducting a large-scale study. We found that CD163 expression was positively associated with the grade of malignancy of glioma. CD163 expression was up-regulated in IDH wild-type glioma and mesenchymal subtype. Gene ontology analysis suggested that CD163-related genes were more involved in immune response and angiogenesis in glioma. Moreover, CD163 showed a positive relationship with stromal and immune cell populations. Kaplan-Meier curves analysis revealed that higher CD163 expression indicated significantly poor survival in glioma and glioblastoma multiforme (GBM). Pearson correlation analysis revealed that CD163 was robustly associated with the immune checkpoints and other macrophage markers. These results demonstrated that CD163 predicts poor prognosis in glioma patients. Additionally, combination of CD163 and immune checkpoints may impair angiogenesis and reverse dysfunctional phenotypes of T cells, which suggest that CD163 may be a promising biomarker and target for immunotherapeutic strategies.