Infiltrating inflammatory cells are highly prevalent within the tumor microenvironment and mediate many processes associated with tumor progression; however, the contribution of specific populations ...remains unclear. For example, the nature and function of tumor-associated neutrophils (TANs) in the cancer microenvironment is largely unknown. The goal of this study was to provide a phenotypic and functional characterization of TANs in surgically resected lung cancer patients. We found that TANs constituted 5%-25% of cells isolated from the digested human lung tumors. Compared with blood neutrophils, TANs displayed an activated phenotype (CD62L(lo)CD54(hi)) with a distinct repertoire of chemokine receptors that included CCR5, CCR7, CXCR3, and CXCR4. TANs produced substantial quantities of the proinflammatory factors MCP-1, IL-8, MIP-1α, and IL-6, as well as the antiinflammatory IL-1R antagonist. Functionally, both TANs and neutrophils isolated from distant nonmalignant lung tissue were able to stimulate T cell proliferation and IFN-γ release. Cross-talk between TANs and activated T cells led to substantial upregulation of CD54, CD86, OX40L, and 4-1BBL costimulatory molecules on the neutrophil surface, which bolstered T cell proliferation in a positive-feedback loop. Together our results demonstrate that in the earliest stages of lung cancer, TANs are not immunosuppressive, but rather stimulate T cell responses.
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses ...PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells. The BET inhibitor limited tumor progression in a cytotoxic T-cell-dependent manner. Together, these data demonstrate a small-molecule approach to block PD-L1 signaling. Given the fact that BET inhibitors have been proven to be safe with manageable reversible toxicity in clinical trials, our findings indicate that pharmacological BET inhibitors represent a treatment strategy for targeting PD-L1 expression.
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•BET inhibitors suppress PD-L1 expression in both immune cells and tumor cells•CD274 is a direct target gene of BRD4•BET inhibitors increase cytotoxic T cell activity to limit tumor progression in mice
Zhu et al. find that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer in mice. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. Together, these data suggest a small-molecule approach to blocking PD-L1 signaling.
Tumor-associated macrophages are major contributors to malignant progression and resistance to immunotherapy, but the mechanisms governing their differentiation from immature myeloid precursors ...remain incompletely understood. In this study, we demonstrate that exosomes secreted by human and mouse tumor-educated mesenchymal stem cells (MSCs) drive accelerated breast cancer progression by inducing differentiation of monocytic myeloid-derived suppressor cells into highly immunosuppressive M2-polarized macrophages at tumor beds. Mechanistically, MSC-derived exosomes but not exosomes from tumor cells contain TGF-β, C1q, and semaphorins, which promote myeloid tolerogenic activity by driving PD-L1 overexpression in both immature myelomonocytic precursors and committed CD206
macrophages and by inducing differentiation of MHC class II
macrophages with enhanced l-Arginase activity and IL-10 secretion at tumor beds. Accordingly, administration of tumor-associated murine MSC-derived exosomes accelerates tumor growth by dampening antitumor immunity, and macrophage depletion eliminates exosome-dependent differences in malignant progression. Our results unveil a new role for MSC-derived exosomes in the differentiation of myeloid-derived suppressor cells into macrophages, which governs malignant growth.
Dendritic cells (DCs) are required to initiate and sustain T cell-dependent anti-cancer immunity. However, tumors often evade immune control by crippling normal DC function. The endoplasmic reticulum ...(ER) stress response factor XBP1 promotes intrinsic tumor growth directly, but whether it also regulates the host anti-tumor immune response is not known. Here we show that constitutive activation of XBP1 in tumor-associated DCs (tDCs) drives ovarian cancer (OvCa) progression by blunting anti-tumor immunity. XBP1 activation, fueled by lipid peroxidation byproducts, induced a triglyceride biosynthetic program in tDCs leading to abnormal lipid accumulation and subsequent inhibition of tDC capacity to support anti-tumor T cells. Accordingly, DC-specific XBP1 deletion or selective nanoparticle-mediated XBP1 silencing in tDCs restored their immunostimulatory activity in situ and extended survival by evoking protective type 1 anti-tumor responses. Targeting the ER stress response should concomitantly inhibit tumor growth and enhance anti-cancer immunity, thus offering a unique approach to cancer immunotherapy.
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•DCs in the tumor microenvironment exhibit ER stress and robust IRE1α/XBP1 activation•DC-intrinsic XBP1 drives primary and metastatic ovarian cancer progression•XBP1 regulates lipid metabolism and antigen presentation by tDCs•Silencing XBP1 in tDC extends host survival by enhancing T cell anti-tumor immunity
Aggressive tumors inhibit protective T cell responses by triggering ER stress-driven lipid metabolism in dendritic cells, thereby impairing antigen presentation and limiting the ability of the immune system to eliminate malignant cells. Relieving ER stress in immune cells may offer a new approach to cancer immunotherapy.
Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic ...syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.
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•Diet enriched with soluble, but not insoluble, fiber induced HCC in dysbiotic mice•Fiber-induced HCC displayed early onset of cholemia and hyperbilirubinemia•Soluble fiber-induced HCC was microbiota-dependent and transmissible to WT mice•Inhibition of gut fermentation and exclusion of dietary soluble fiber prevented HCC
Dysregulated fermentation of dietary soluble fibers by gut microbiota induces cholestasis, hepatic inflammation, and liver cancer in mice.
The microenvironment of pancreatic cancer adenocarcinoma (PDAC) is highly desmoplastic with distinct tumor‐restraining and tumor‐promoting fibroblast subpopulations. Re‐education rather than ...indiscriminate elimination of these fibroblasts has emerged as a new strategy for combination therapy. Here, we studied the effects of global loss of profibrotic noncoding regulatory microRNA‐21 (miR‐21) in K‐Ras‐driven p53‐deleted genetically engineered mouse models of PDAC. Strikingly, loss of miR‐21 accelerated tumor initiation via mucinous cystic neoplastic lesions and progression to locally advanced invasive carcinoma from which animals precipitously succumbed at an early age. The absence of tumor‐restraining myofibroblasts and a massive infiltrate of immune cells were salient phenotypic features of global miR‐21 loss. Stromal miR‐21 activity was required for induction of tumor‐restraining myofibroblasts in in vivo isograft transplantation experiments. Low miR‐21 expression negatively correlated with a fibroblast gene expression signature and positively with an immune cell gene expression signature in The Cancer Genome Atlas PDAC data set (n = 156) mirroring findings in the mouse models. Our results exposed an overall tumor‐suppressive function of miR‐21 in in vivo PDAC models. These results have important clinical implications for anti‐miR‐21‐based inhibitory therapeutic approaches under consideration for PDAC and other cancer types. Mechanistic dissection of the cell‐intrinsic role of miR‐21 in cancer‐associated fibroblasts and other cell types will be needed to inform best strategies for pharmacological modulation of miR‐21 activity to remodel the tumor microenvironment and enhance treatment response in PDAC.
What's new?
The opposing tumor‐restraining and tumor‐promoting role of distinct subpopulations of cancer‐associated fibroblasts (CAFs) has emerged as a new paradigm in the biology of pancreatic cancer ductal adenocarcinoma (PDAC). In addition, microRNA‐21 (miR‐21), expressed in CAFs, is frequently upregulated in PDAC. This preclinical study in genetically engineered PDAC mice shows that global loss of profibrotic TGF‐β‐inducible miR‐21 is required for the activation of tumor‐restraining fibroblasts. The data reveal a profibrotic yet overall tumor suppressive function for miR‐21 in vivo. The findings are relevant for anti‐miR‐21‐based therapeutic strategies currently under investigation for various cancer types, including PDAC.
The gene encoding ARID1A, a chromatin remodeler, shows one of the highest mutation rates across many cancer types. Notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas, which ...currently have no effective therapy. To date, clinically applicable targeted cancer therapy based on ARID1A mutational status has not been described. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer cells and that ARID1A mutational status correlated with response to the EZH2 inhibitor. We identified PIK3IP1 as a direct target of ARID1A and EZH2 that is upregulated by EZH2 inhibition and contributed to the observed synthetic lethality by inhibiting PI3K-AKT signaling. Importantly, EZH2 inhibition caused regression of ARID1A-mutated ovarian tumors in vivo. To our knowledge, this is the first data set to demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. Our data indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for cancers involving ARID1A mutations.
Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in ...humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer. These APC-like “hybrid neutrophils,” which originate from CD11b+CD15hiCD10−CD16low immature progenitors, are able to cross-present antigens, as well as trigger and augment anti-tumor T cell responses. Interferon-γ and granulocyte-macrophage colony-stimulating factor are requisite factors in the tumor that, working through the Ikaros transcription factor, synergistically exert their APC-promoting effects on the progenitors. Overall, these data demonstrate the existence of a specialized TAN subset with anti-tumor capabilities in human cancer.
•Lung tumors accumulate a subset of TANs with a granulocyte and APC hybrid phenotype•APC-like hybrid neutrophils are able to stimulate the anti-tumor T cell responses•IFN-γ and GM-CSF are requisite factors for the development of hybrid neutrophils•Ikaros negatively regulates the development of hybrid neutrophils from progenitors
Singhal et al. identify a subset of tumor-associated neutrophils (TANs) that can cross-present tumor antigens and activate anti-tumor T cells in stage I/II human lung cancer. The induction of these hybrid TANs from progenitors requires GM-CSF and IFN-γ and reduction of Ikaros.
Due to their cytotoxic activities, many anticancer drugs cause extensive damage to the intestinal mucosa and have antibiotic activities. Here, we show that cisplatin induces significant changes in ...the repertoire of intestinal commensal bacteria that exacerbate mucosal damage. Restoration of the microbiota through fecal‐pellet gavage drives healing of cisplatin‐induced intestinal damage. Bacterial translocation to the blood stream is correspondingly abrogated, resulting in a significant reduction in systemic inflammation, as evidenced by decreased serum IL‐6 and reduced mobilization of granulocytes. Mechanistically, reversal of dysbiosis in response to fecal gavage results in the production of protective mucins and mobilization of CD11b+ myeloid cells to the intestinal mucosa, which promotes angiogenesis. Administration of Ruminococcus gnavus, a bacterial strain selectively depleted by cisplatin treatment, could only partially restore the integrity of the intestinal mucosa and reduce systemic inflammation, without measurable increases in the accumulation of mucin proteins. Together, our results indicate that reconstitution of the full repertoire of intestinal bacteria altered by cisplatin treatment accelerates healing of the intestinal epithelium and ameliorates systemic inflammation. Therefore, fecal microbiota transplant could paradoxically prevent life‐threatening bacteremia in cancer patients treated with chemotherapy.
Fecal microbiota transplant accelerates intestinal healing and prevents bacteriemia after cisplatin treatment
B cells and cancer Engelhard, Victor; Conejo-Garcia, Jose R.; Ahmed, Rafi ...
Cancer cell,
10/2021, Letnik:
39, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Tumor-infiltrating B cells complement T cell-mediated antitumor immunity. A panel of experts share their views on the complexity of B cells within the tumor microenvironment, the variety of ...mechanisms by which these cells control tumor growth, their organization in tertiary lymphoid structures, and their association with immunotherapy response.
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