Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with extremely skewed ethnic and geographic distributions. Increasing evidence indicates that targeting the tumor microenvironment (TME) ...represents a promising therapeutic approach in NPC, highlighting an urgent need to deepen the understanding of the complex NPC TME. Here, we generated single-cell transcriptome profiles for 7581 malignant cells and 40,285 immune cells from fifteen primary NPC tumors and one normal sample. We revealed malignant signatures capturing intratumoral transcriptional heterogeneity and predicting aggressiveness of malignant cells. Diverse immune cell subtypes were identified, including novel subtypes such as CLEC9A
dendritic cells (DCs). We further revealed transcriptional regulators underlying immune cell diversity, and cell-cell interaction analyses highlighted promising immunotherapeutic targets in NPC. Moreover, we established the immune subtype-specific signatures, and demonstrated that the signatures of macrophages, plasmacytoid dendritic cells (pDCs), CLEC9A
DCs, natural killer (NK) cells, and plasma cells were significantly associated with improved survival outcomes in NPC. Taken together, our findings represent a unique resource providing in-depth insights into the cellular heterogeneity of NPC TME and highlight potential biomarkers for anticancer treatment and risk stratification, laying a new foundation for precision therapies in NPC.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Defects in natural killer (NK) cell functions are necessary for tumor immune escape, but their underlying regulatory mechanisms in human cancers remain largely unknown. Here we show, in detailed ...studies of NK cells in 294 untreated patients with hepatocellular carcinoma (HCC), that accumulation of functional NK cells in HCC tissues could predict improved survival of patients. However, in patients with advanced‐stage HCC, NK cells were significantly decreased in number with impaired tumor necrosis factor alpha (TNF‐α) and interferon‐gamma (IFN‐γ) production. High infiltration of peritumoral stroma monocytes/macrophages was positively correlated with impaired functional activities of NK cells in intratumoral areas. Further kinetic experiments revealed that soon after exposure to tumor‐derived monocytes, NK cells underwent a rapid, transient activation, but then they became exhausted, and eventually died. The monocytes from HCC tissues, but not from nontumoral liver, strongly express CD48 proteins; and such monocyte‐induced NK cell dysfunction was markedly attenuated by blocking CD48 receptor 2B4 on NK cells, but not by blockade of NKG2D and NKp30. Conclusion: These data reveal that human NK cells are regulated by a fine‐tuned collaborative action between different types of immune cells, which may reflect a novel immune‐escape mechanism by which tumors dynamically regulate their functions at distinct tumor microenvironments. (HEPATOLOGY 2013)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Macrophages (Mphi) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental ...process of Mphi to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mphi in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1(+) and HLA-DR(high) on tumor-infiltrating monocytes. Autocrine tumor necrosis factor alpha and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1(+) monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mphi may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.
B cells constitute a major component of tumor-infiltrating leukocytes. However, the influence of these cells on malignancy is currently under debate, reflecting the heterogeneity of B cell subsets in ...tumors. With recent advances, it becomes apparent that this debate includes not only the evaluation of B cells themselves, but also the underlying immune microenvironment network, which scripts the highly heterogeneous B cell populations in tumors and directs the roles of those sub-populations in disease progression and clinical treatment. In this review, we summarize recent findings on the heterogeneous subset composition of B cells in both human and mouse tumor models and their different impacts on disease progression. We further describe the multidimensional interplays between B cells and other immune cells in the tumor microenvironment, which account for the regulation of B cell differentiation and function in situ. We also assess the potential influences of distinct sub-tumor locations on B cell function in primary tumors during development and those under immunotherapy treatment. Illuminating the heterogeneous nature of B cell subset composition, generation, localization, and related immune network in tumor is of immense significance for comprehensively understanding B cell response in tumor and designing more efficacious cancer immunotherapies.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Microbiota has been implicated in the regulation of tumor progression and therapeutic efficacy. However, the effect of microbiota on disease progression is context dependent, differing according to ...tumor types, therapeutic regimens, and composition of the microbiota, calling for a deeper understanding of host-microbiome interactions. Previous studies have demonstrated that gut microbiota influences disease progression by regulating local and systemic immunity. Notably, with the advent of next-generation sequencing technology, intratumoral microbiota has also been found and constitutes an important component of the tumor microenvironment. In this review, we summarize recent knowledge about the identification of intra-tumor microbiota and discuss the role of gut and intratumoral microbiota in solid tumors in the angle of immune microenvironment interaction. Furthermore, we discuss how these findings may benefit current anti-cancer approaches. Key problems to be solved in ongoing and future research are highlighted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
B cells consistently represent abundant cellular components in tumors; however, direct evidence supporting a role for B cells in the immunopathogenesis of human cancers is lacking, as is specific ...knowledge of their trafficking mechanisms. Here, we demonstrate that chemokine (C‐X‐C motif) receptor 3–positive (CXCR3+) B cells constitute approximately 45% of B‐cell infiltrate in human hepatocellular carcinoma (HCC) and that their levels are positively correlated with early recurrence of HCC. These cells selectively accumulate at the invading edge of HCC and undergo further somatic hypermutation and immunoglobulin G–secreting plasma cell differentiation. Proinflammatory interleukin‐17+ cells are important for the induction of epithelial cell–derived CXCR3 ligands CXCL9, CXCL10, and CXCL11, which subsequently promote the sequential recruitment and further maturation of CXCR3+ B cells. More importantly, we provide evidence that CXCR3+ B cells, but not their CXCR3– counterparts, may operate in immunoglobulin G–dependent pathways to induce M2b macrophage polarization in human HCC. Depletion of B cells significantly suppresses M2b polarization and the protumorigenic activity of tumor‐associated macrophages and restores the production of antitumorigenic interleukin‐12 by those cells in vivo. Conclusion: Selective recruitment of CXCR3+ B cells bridges proinflammatory interleukin‐17 response and protumorigenic macrophage polarization in the tumor milieu, and blocking CXCR3+ B‐cell migration or function may help defeat HCC.(Hepatology 2015;62:1779–1790)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.
We performed 5'and VDJ single-cell ...RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.
Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1
CD8
T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8
T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells' cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of
recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.
True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.
Background & Aims Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with ...extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive. Methods A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies. Results Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues; this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo. Conclusions These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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•Peritumoral monocytes in human HCC preferentially upregulate aerobic glycolysis.•Aerobic glycolysis induces PD-L1 expression via the PFKFB3-NF-κB pathway.•Tumor derived hyaluronan ...fragments induce glycolytic activation in monocytes.•Levels of PFKFB3+CD68+ cell infiltration predict disease progression of human HCC.
Programmed cell death 1 ligand 1 (PD-L1) expression on antigen-presenting cells is essential for T cell impairment, and PD-L1-expressing macrophages may mechanistically shape and therapeutically predict the clinical efficacy of PD-L1 or programmed cell death 1 blockade. We aimed to elucidate the mechanisms underlying PD-L1 upregulation in human tumor microenvironments, which remain poorly understood despite the clinical success of immune checkpoint inhibitors.
Monocytes/macrophages were purified from peripheral blood, non-tumor, or paired tumor tissues of patients with hepatocellular carcinoma (HCC), and their possible glycolytic switch was evaluated. The underlying regulatory mechanisms and clinical significance of metabolic switching were studied with both ex vivo analyses and in vitro experiments.
We found that monocytes significantly enhanced the levels of glycolysis at the peritumoral region of human HCC. The activation of glycolysis induced PD-L1 expression on these cells and subsequently attenuated cytotoxic T lymphocyte responses in tumor tissues. Mechanistically, tumor-derived soluble factors, including hyaluronan fragments, induced the upregulation of a key glycolytic enzyme, PFKFB3, in tumor-associated monocytes. This enzyme not only modulated the cellular metabolic switch but also mediated the increased expression of PD-L1 by activating the nuclear factor kappa B signaling pathway in these cells. Consistently, the levels of PFKFB3+CD68+ cell infiltration in peritumoral tissues were negatively correlated with overall survival and could serve as an independent prognostic factor for survival in patients with HCC.
Our results reveal a mechanism by which the cellular metabolic switch regulates the pro-tumor functions of monocytes in a specific human tumor microenvironment. PFKFB3 in both cancer cells and tumor-associated monocytes is a potential therapeutic target in human HCC.
Programmed cell death 1 ligand 1 (PD-L1) expressed on antigen-presenting cells, rather than tumor cells, has been reported to play an essential role in checkpoint blockade therapy. A fundamental understanding of mechanisms that regulate the expression of PD-L1 on tumor-infiltrating monocytes/macrophages will undoubtedly lead to the possibility of developing novel PD-L1 blockade strategies with high specificity and efficiency. The current study unveils a novel mechanism by which metabolic switching links immune activation responses to immune tolerance in the tumor milieu, identifying potential targets for future immune-based anti-cancer therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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