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One of the difficulties in the treatment of hepatocellular carcinoma is that it is impossible to eliminate the inhibitory effect of the tumor microenvironment on immune response. Therefore, it is particularly important to understand the formation process of the tumor microenvironment. Chronic inflammation is the core factor of cancer occurrence and the leading stage of inflammation–cancer transformation, and the natural killer cell subsets play an important role in it. Our study confirmed that in the stage of chronic liver injury, the local immunosuppressive microenvironment of the liver (i.e. the damaged microenvironment) has been formed, but this inhibitory effect is only for peripheral natural killer cells and has no effect on tissue-resident natural killer subsets. The markers of damage microenvironment are the same as those of tumor microenvironment. [ABSTRACT FROM AUTHOR]

NK cells are lymphocytes involved in the innate and adaptative immune response. These cells are located in peripheral blood and tissues with ample functions, from immune vigilant to tolerogenic reactions. In the endometrium, NK cell populations vary depending on age, hormones, and inflammation. When pregnancy occurs, tissue-resident NK cells and conventional NK cells are recruited to protect the fetus, a tolerogenic response. On the contrary, in the inflamed endometrium, various inflammatory cells down-regulate NK tolerance and impair embryo implantation. Therefore, NK cells’ pharmacological modulation is difficult to achieve. Several strategies have been used, from progesterone, lipid emulsions to steroids; the success has not been as expected. However, new therapeutic approaches have been proposed to decrease the endometrial inflammatory burden and increase pregnancy success based on understanding NK cell physiology.

Colorectal cancer (CRC) is one of the most common cancer worldwide, with a growing impact on public health and clinical management. Immunotherapy has shown promise in the treatment of advanced cancers, but needs to be improved for CRC, since only a limited fraction of patients is eligible for treatment, and most of them develop resistance due to progressive immune exhaustion. Here, we identify the transcriptional, molecular, and cellular traits of the immune exhaustion associated with CRC and determine their relationships with the patient's clinic-pathological profile. Bioinformatic analyses of RNA-sequencing data of 594 CRCs from TCGA PanCancer collection, revealed that, in the wide range of immune exhaustion genes, those coding for PD-L1 , LAG3 and T-bet were associated (Cramér's V=0.3) with MSI/dMMR tumors and with a shorter overall survival (log-rank test: p= 0.0004, p =0.0014 and p =0.0043, respectively), whereas high levels of expression of EOMES , TRAF1 , PD-L1 , FCRL4, BTLA and SIGLEC6 were associated with a shorter overall survival (log-rank test: p =0.0003, p =0.0188, p =0.0004, p =0.0303, p =0.0052 and p =0.0033, respectively), independently from the molecular subtype of CRC. Expression levels of PD-L1, PD-1, LAG3, EOMES, T-bet , and TIGIT were significantly correlated with each other and associated with genes coding for CD4+ and CD8+CD3+ T cell markers and NKp46+CD94+EOMES+T-bet+ cell markers, (OR >1.5, p <0.05), which identify a subset of group 1 innate lymphoid cells, namely conventional (c)NK cells. Expression of TRAF1 and BTLA co-occurred with both T cell markers, CD3γ, CD3δ, CD3ε, CD4 , and B cell markers, CD19, CD20 and CD79a (OR >2, p <0.05). Expression of TGFβ1 was associated only with CD4 + and CD8+CD3ε+ T cell markers (odds ratio >2, p <0.05). Expression of PD-L2 and IDO1 was associated (OR >1.5, p <0.05) only with cNK cell markers, whereas expression of FCRL4, SIGLEC2 and SIGLEC6 was associated (OR >2.5; p <0.05) with CD19+CD20+CD79a+ B cell markers. Morphometric examination of immunostained CRC tissue sections, obtained from a validation cohort of 53 CRC patients, substantiated the biostatistical findings, showing that the highest percentage of immune exhaustion gene expressing cells were found in tumors from short-term survivors and that functional exhaustion is not confined to T lymphocytes, but also involves B cells, and cNK cells. This concept was strengthened by CYBERSORTx analysis, which revealed the expression of additional immune exhaustion genes, in particular FOXP1, SIRT1, BATF, NR4A1 and TOX , by subpopulations of T, B and NK cells. This study provides novel insight into the immune exhaustion landscape of CRC and emphasizes the need for a customized multi-targeted therapeutic approach to overcome resistance to current immunotherapy. [ABSTRACT FROM AUTHOR]

The liver is a major metastatic target organ, and little is known about the role of immunity in controlling hepatic metastases. Here, we discovered that the concerted and nonredundant action of two innate lymphocyte subpopulations, conventional natural killer cells (cNKs) and tissue-resident type I innate lymphoid cells (trILC1s), is essential for antimetastatic defense. Using different preclinical models for liver metastasis, we found that trILC1 controls metastatic seeding, whereas cNKs restrain outgrowth. Whereas the killing capacity of trILC1s was not affected by the metastatic microenvironment, the phenotype and function of cNK cells were affected in a cancer type-specific fashion. Thus, individual cancer cell lines orchestrate the emergence of unique cNK subsets, which respond differently to tumorderived factors. Our findings will contribute to the development of therapies for liver metastasis involving hepatic innate cells. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are the most abundant lymphocytes at the maternal-fetal interface. Epidemiological data implicate NK cells in human pregnancy outcomes. Discoveries using mouse NK cells have guided subsequent advances in human NK cell biology. However, it remains challenging to identify mouse and human uterine NK (uNK) cell function(s) because of the dynamic changes in the systemic-endocrinological and local uterine structural microenvironments during pregnancy. This review discusses functional similarities and differences between mouse and human NK cells at the maternal-fetal interface.

Autoimmune hepatitis (AIH) is a chronic autoimmune disease with the primary focus on autoreactive Th1-mediated response and cytotoxic T cells reaction. The contribution of natural killer cells (NK cells) to AIH remains poorly understood. In this project, we revealed that the frequency of peripheral NK cells, more accurately CD56 dim NK subset, was reduced in AIH patients. The reduction of CD56 dim NK was negatively correlated with disease progression. In experimental autoimmune hepatitis (EAH), hepatic accumulation of NK cells is observed along with a decrease of NK cells in the periphery. In addition, infiltrated NK cells are almost conventional CXCR3 − NK cells, the counterpart of CD56 dim NK cells in the human. Furthermore, conventional CXCR3-NK cells of infiltration and liver resident NK cells are activated progressively at active phase. Therefore, recruitment of cytotoxic NK cells into the liver, but not liver resident NK cells expansion, may partly account for AIH progression. [ABSTRACT FROM AUTHOR]

Keywords: conventional NK cells; tissue resident NK cells; innate lymphoid cells; tissue microenvironment; NK receptors As described in detail by Mikulak et al., human liver contains three NK cell populations showing transcriptional and phenotypic differences: liver tr-NK cells, memory-like NK cells and recirculating c-NK cells. Although this issue could be the subject of a dedicated Research Topic, we here present a few contributions highlighting two specific components when considering any NK cell-based immunotherapeutic strategy: NK cell checkpoints and tumor infiltration by NK cells. Conventional NK cells, tissue resident NK cells, innate lymphoid cells, tissue microenvironment, NK receptors. [Extracted from the article]

Summary The tolerogenic microenvironment of the liver is associated with impaired hepatic T cell function. Here, we examined the contribution of liver-resident natural killer (LrNK) cells, a prominent hepatic NK cell compartment, to T cell antiviral responses in the liver. The number of virus-specific T cells increased in LrNK-cell-deficient mice during both acute and chronic lymphocytic choriomeningitis virus infection. Upon infection with adenovirus, hepatic T cells from these mice produced more cytokines, which was accompanied by reduced viral loads. Transfer of LrNK cells into LrNK-cell-deficient or wild-type mice inhibited hepatic T cell function, resulting in impaired viral clearance, whereas transfer of conventional NK cells promoted T cell antiviral responses. LrNK-cell-mediated inhibition of T cell function was dependent on the PD-1-PD-L1 axis. Our findings reveal a role for LrNK cells in the regulation of T cell immunity and provide insight into the mechanisms of immune tolerance in the liver. Graphical Abstract Highlights • Expression of negative immune-regulatory genes is enriched in LrNK cells • Virus-specific T cell responses are enhanced in LrNK-cell-deficient mice • LrNK cell transfer inhibits hepatic T cell responses against LCMV and adenoviruses • Blockade of PD-L1 abrogates the inhibitory effect of LrNK cells on T cells Zhou et al. find that during viral infection, liver-resident NK (LrNK) cells inhibit the function of hepatic T cells via PD-1-PD-L1 interactions. Their findings reveal a role for LrNK cells in the regulation of T cell immunity and provide insight into the mechanisms of immune tolerance in the liver. [ABSTRACT FROM AUTHOR]