Tertiary lymphoid structures (TLSs) are a common finding in non-small cell lung cancer (NSCLC) and are predictors of favourable clinical outcome. Here we show that NCR þ innate lymphoid cell (ILC)-3 are present in the lymphoid infiltrate of human NSCLC and are mainly localized at the edge of tumour-associated TLSs. This intra-tumoral lymphocyte subset is endowed with lymphoid tissue-inducing properties and, on activation, produces IL-22, TNF-a, IL-8 and IL-2, and activates endothelial cells. Tumour NCR þ ILC3 may interact with both lung tumour cells and tumour-associated fibroblasts, resulting in the release of cytokines primarily on engagement of the NKp44-activating receptor. In patients, NCR þ ILC3 are present in significantly higher amounts in stage I/II NSCLC than in more advanced tumour stages and their presence correlate with the density of intratumoral TLSs. Our results indicate that NCR þ ILC3 accumulate in human NSCLC tissue and might contribute to the formation of protective tumour-associated TLSs.

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BaCKgRoUND aND aIMS: Natural killer (NK) cells play a crucial role in the clearance of human viruses but their activity is significantly impaired in patients infected with chronic hepatitis B (CHB). Cooperation with dendritic cells (DCs) is pivotal for obtaining optimal NK cell antiviral function; thus, we investigated whether HBV might impact the ability of DCs to sustain NK cell functions. appRoaCH aND ReSUltS: Human DCs were poor stimulators of interferon-gamma (IFNγ) production by NK cells when exposed to HBV, while maintaining the capability to trigger NK cell cytotoxicity. HBV prevented DC maturation but did not affect their expression of human leukocyte antigen class I, thus allowing DCs to evade NK cell lysis. Tolerogenic features of DCs exposed to HBV were further supported by their increased expression of IL-10 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase, which contributed to the impairment of DC-mediated NK cell IFNγ production and proliferation, respectively. HBV could also inhibit the expression of inducible immunoproteasome (iP) subunits on DCs. In fact, NK cells could induce iP subunit expression on DCs, but they failed in the presence of HBV. Remarkably, circulating blood DC antigen1 (BDCA1) + DCs isolated from patients with CHB were functionally compromised, hence altering, in turn, NK cell responses. CoNClUSIoNS:The abnormal NK-DC interplay caused by HBV may significantly impair the efficacy of antiviral immune response in patients with CHB. (Hepatology 2021;74:550-565). HBV is a major cause of inflammatory liver disease of variable severity that affects millions of people worldwide. Despite the availability of vaccine, more than 257 million people are still infected with HBV. (1) The pathophysiology of HBV infection is complex and closely linked to host immune response. An ineffective and weak immune response toward HBV is thought to be the fundamental underlying cause for evolution of HBV infection until the establishment of chronic disease. (2,3) Progression of persistent infection together with cell death and regeneration of infected hepatocytes succeed one another, leading to chronic inflammation and fibrosis often associated with the risk of developing liver cirrhosis and hepatocellular carcinoma. (4)