Dysregulation of NK and CD8+T Cells by the Microbiota Promotes the Progression of Lung Cancer.

The commensal microbiota is involved in maintaining local pulmonary immune homeostasis under physiological conditions. Alterations in the amount and dominant species of the microbiota can reshape the immune response of the body and lead to a variety of lung diseases, including cancer. The precise mechanisms by which microbiota regulate immune cells during the progression of lung cancer remain obscure. In this study, using a Kras-mutated-driven spontaneous lung cancer mouse model, we found that the depletion of microbiota can alleviate lung lesions in Kras-mutated mice at different stages of tumour development. Long-term antibiotic treatment significantly reduced the number NK cells and IFN-γ secretion and CD8+T cells in the lungs of wild-type (WT) mice, suggesting that the microbiota plays an important role in maintaining homeostasis of NK cells and CD8+T cells under normal conditions. However, in Kras-mutated mice, the altered pulmonary immune microenvironment resulted in a microbiota disorder and in the loss of the ability to regulate the immune responses of NK cells and CD8+T cells, thus promoting the occurrence and development of lung cancer. Further mechanistic studies have shown that the CXCL9-CXCR3 axis participated in the local recruitment of NK cells and CD8+T cells by the microbiota into lung tissues in Kras-mutated mice. Our findings reveal the role of the microbiota in reshaping tumour-related immune responses involving NK cells and CD8+T cells and shed light on the clinical immunotherapy of lung cancer.

Increased interleukin-17A-producing γδT cells predict favorable survival in elderly patients with LUAD and LUSC.

PURPOSE: Aging is closely related to the occurrence of many diseases, including cancer, and involves changes in the immune microenvironment. γδT cells are important components of resident lymphocytes in mucosal tissues. However, little is known about the effects that the aged lung has on γδT cells and their prognostic significance in non-small cell lung cancer. METHODS: In the current study, the expression of γδTCR and IL-17A was measured by immunohistochemistry in paraffin-embedded lung tissues from 168 patients with adenocarcinoma (LUAD) and 144 patients with squamous cell carcinoma (LUSC). Furthermore, gene transcription patterns in LUAD and LUSC tumors and normal controls were extracted from TCGA and GTEx databases and were analyzed. RESULTS: High frequency of γδT cells was observed in patients with LUAD and LUSC, whereas the levels of CD4 + T cells, CD8 + T cells and CD56 + cells were decreased. Elevated γδT cells in tumors were mainly IL-17A-releasing γδT17 cells, which were found to be enriched in aged patients. High γδT cell levels positively corelated with the overall survival (OS) of patients, especially the 5-year OS in the elderly. Further analysis of gene transcription patterns indicated that increased expression of LTBR, HES1, RORC, CCR6, IL1, and IL23A may contribute to the transformation of the tumor microenvironment in a manner conducive to γδT17 cell development and differentiation. Finally, gene analysis between different age groups revealed that the expression of CCR6 and IL7 in LUAD, as well as Hes1, IL7, and IL23A in LUSC, were remarkably higher in elderly (age ≥ 60 years) than in younger individuals (age < 60 years). CONCLUSION: Our findings suggest that intrinsic alterations in the aging lung lead to γδT17 cell enrichment, which subsequently may exert anti-tumor effects in the elderly.

Corrigendum: Innate Immune Cells in the Esophageal Tumor Microenvironment.

[This corrects the article DOI: 10.3389/fimmu.2021.654731.].

Innate Immune Cells in the Esophageal Tumor Microenvironment.

Esophageal cancer (EC) is one of the most common mucosa-associated tumors, and is characterized by aggressiveness, poor prognosis, and unfavorable patient survival rates. As an organ directly exposed to the risk of foodborne infection, the esophageal mucosa harbors distinct populations of innate immune cells, which play vital roles in both maintenance of esophageal homeostasis and immune defense and surveillance during mucosal anti-infection and anti-tumor responses. In this review, we highlight recent progress in research into innate immune cells in the microenvironment of EC, including lymphatic lineages, such as natural killer and γδT cells, and myeloid lineages, including macrophages, dendritic cells, neutrophils, myeloid-derived suppressor cells, mast cells and eosinophils. Further, putative innate immune cellular and molecular mechanisms involved in tumor occurrence and progression are discussed, to highlight potential directions for the development of new biomarkers and effective intervention targets, which can hopefully be applied in long-term multilevel clinical EC treatment. Fully understanding the innate immunological mechanisms involved in esophageal mucosa carcinogenesis is of great significance for clinical immunotherapy and prognosis prediction for patients with EC.

The Emerging Role of Tissue-Resident Memory CD8+ T Lymphocytes in Human Digestive Tract Cancers.

Malignant digestive tract tumors are a great threat to human public health. In addition to surgery, immunotherapy brings hope for the treatment of these tumors. Tissue-resident memory CD8+ T (Trm) cells are a focus of tumor immunology research and treatment due to their powerful cytotoxic effects, ability to directly kill epithelial-derived tumor cells, and overall impact on maintaining mucosal homeostasis and antitumor function in the digestive tract. They are a group of noncirculating immune cells expressing adhesion and migration molecules such as CD69, CD103, and CD49a that primarily reside on the barrier epithelium of nonlymphoid organs and respond rapidly to both viral and bacterial infection and tumorigenesis. This review highlights new research exploring the role of CD8+ Trm cells in a variety of digestive tract malignant tumors, including esophageal cancer, gastric cancer, colorectal cancer, and hepatocellular carcinoma. A summary of CD8+ Trm cell phenotypes and characteristics, tissue distribution, and antitumor functions in different tumor environments is provided, illustrating how these cells may be used in immunotherapies against digestive tract tumors.

Suppression of Natural Killer Cell Activity by Regulatory NKT10 Cells Aggravates Alcoholic Hepatosteatosis.

We and others have found that the functions of hepatic natural killer (NK) cells are inhibited but invariant NKT (iNKT) cells become activated after alcohol drinking, leaving a possibility that there exists interplay between NK cells and iNKT cells during alcoholic liver disease. Here, in a chronic plus single-binge ethanol consumption mouse model, we observed that NK cells and interferon-γ (IFN-γ) protected against ethanol-induced liver steatosis, as both wild-type (WT) mice treated with anti-asialo GM1 antibody and IFN-γ-deficient GKO mice developed more severe alcoholic fatty livers. As expected, IFN-γ could directly downregulate lipogenesis in primary hepatocytes in vitro. On the contrary, iNKT cell-deficient Jα18-/- or interleukin-10 (IL-10)-/- mice showed fewer alcoholic steatosis, along with the recovered number and IFN-γ release of hepatic NK cells, and exogenous IL-10 injection was sufficient to compensate for iNKT cell deficiency. Furthermore, NK cell depletion in Jα18-/- or IL-10-/- mice caused more severe hepatosteatosis, implying NK cells are the direct effector cells to inhibit liver steatosis. Importantly, adoptive transfer of iNKT cells purified from normal but not IL-10-/- mice resulted in suppression of the number and functions of NK cells and aggravated alcoholic liver injury in Jα18-/- mice, indicating that IL-10-producing iNKT (NKT10) cells are the regulators on NK cells. Conclusion: Ethanol exposure-triggered NKT10 cells antagonize the protective roles of NK cells in alcoholic hepatosteatosis.

Invariant NKT cells promote alcohol-induced steatohepatitis through interleukin-1ß in mice.

BACKGROUND & AIMS: It was reported that alcohol consumption activated the NLRP3 inflammasome in Kupffer cells, leading to mature interleukin (IL)-1ß release in alcoholic liver injury; however, how IL-1ß promotes liver injury remains unclear. METHODS: We investigated the role of IL-1ß in alcoholic steatohepatitis by using a chronic plus single-binge ethanol consumption mouse model. RESULTS: Here, liver steatosis was accompanied by notably increased invariant natural killer T (iNKT) cell numbers and activation, and iNKT-deficient Jα18(-/-) mice developed less alcohol-induced steatosis, with reduced liver inflammation and neutrophil infiltration. Kupffer cells and IL-1ß were required for the hepatic iNKT accumulation, as either blocking IL-1ß signaling with a recombinant IL-1 receptor antagonist (IL-1Ra), depleting Kupffer cells by clodronate liposomes, or specifically silencing IL-1ß in Kupffer cells by nanoparticle-encapsulated siRNA, resulted in inhibited hepatic iNKT cell accumulation and activation, as well as amelioration of alcoholic fatty liver. In addition, IL-1ß overexpression in hepatocytes was sufficient to compensate for Kupffer cell depletion. Increased gene and protein expression of mature IL-1ß correlated with elevated expression of the NLRP3 inflammasome components NLRP3, ASC, and cleaved caspase-1 in Kupffer cells from ethanol-exposed wild-type mice. NLRP3 deficiency led to the attenuation of alcoholic steatosis, similarly as Kupffer cell depletion, almost without hepatic NKT cells. CONCLUSIONS: After alcohol-exposure Kupffer cell-derived IL-1ß triggered by NLRP3 activation, recruits and activates hepatic iNKT cells, subsequently promoting liver inflammation and neutrophil infiltration, and inducing alcoholic liver injury.