Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

Mantovani, Stefania; Oliviero, Barbara; Lombardi, Andrea; Varchetta, Stefania; Mele, Dalila; Sangiovanni, A.; Rossi, Giorgio; Donadon, Matteo; Torzilli, Guido; Soldani, Cristiana; Porta, Camillo; Pedrazzoli, Paolo; Chiellino, Silvia; Santambrogio, Roberto; Opocher, Enrico; Maestri, Marcello; Bernuzzi, Stefano; Rossello, Armando; Clément, Sophie; Vito, Claudio De; Rubbia‐Brandt, Laura; Negro, Francesco; Mondelli, Mario U.

doi:10.1002/hep.30235

Cited by 54 publications

(73 citation statements)

References 48 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[60][61][62] Elevated preoperative peripheral blood neutrophil-to-lymphocyte (NLR) ratio is also a poor prognostic factor for intrahepatic and extrahepatic CCA, [63][64][65][66] as well as in patients with advanced CCA undergoing chemotherapy. 67 73,74 Furthermore, immunotherapy with infusion of activated allogeneic NK cells has also been performed in HCC patients with promising outcomes. 75,76 However, before such treatments can be employed in CCA, it is necessary to determine if NK cells have the capacity to infiltrate CCA, which NK cell receptor-ligand interactions are important for recognition of CCA, and how NK cells are affected by evasion strategies employed by the tumour and its microenvironment.…”

Section: The Role Of the Innate Immune Sys Tem In CC Amentioning

confidence: 99%

The tumour microenvironment and immune milieu of cholangiocarcinoma

Fabris

Perugorria

Mertens

et al. 2019

Liver International

128

124

View full text Add to dashboard Cite

Tumour microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumour microenvironment comprises not only stromal cells, mainly cancer‐associated fibroblasts, but also immune cells of both the innate and adaptive system (tumour‐associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodelled extracellular matrix, where the tumour cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely because of the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumour‐promoting function of the tumour microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma.

show abstract

Section: The Role Of the Innate Immune Sys Tem In CC Amentioning

confidence: 99%

The tumour microenvironment and immune milieu of cholangiocarcinoma

Fabris

Perugorria

Mertens

et al. 2019

Liver International

128

124

View full text Add to dashboard Cite

show abstract

“…Other studies point to additional receptor-ligand axes, such as the DNAX Accessory Molecule-1 (DNAM-1) activating NKR and its ligand CD155, in HCC development [5]. Our recently published data point to an altered expression and function of the NKp30 activating receptor in circulating and resident NK cells of HCC patients, the former expressing an inappropriately high level of the Tim-3 exhaustion marker [6]. This, together with decreased expression of the major NKp30 ligand B7-H6 in liver cancer tissue relative to the stage of the disease suggests that this ligand play a major role in cancer surveillance.…”

Section: Introductionmentioning

confidence: 79%

“…Moreover, available evidence showed a positive correlation between the frequency of circulating and intrahepatic NK cells and survival in patients with HCC [4]. Interestingly, HCC cells express ligands of several activating NK receptors (NKR), including NKp30, natural killer receptor group 2, member D (NKG2D) and DNAM-1 such as the B7 protein homolog 6, the major histocompatibility complex class I chain-related protein A and B (MICA/B) and CD155, respectively, whose expression can correlate with the outcome of the disease [5,6]. Despite these findings supporting a role for NK cells in HCC immune surveillance, the pathogenetic mechanisms leading to HCC development and progression are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Mantovani

Oliviero

Varchetta

et al. 2020

Cancers

Self Cite

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri-and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.

show abstract

“…B7-H6 expressed by HCC cells was shown to down-modulate activating NKp30 and to increase insoluble form in advanced stages. 28 The abundance of tumour-infiltrating T cells has been related to survival in HCC patients, [29][30][31][32] but anti-tumour T cell response is impaired by tolerance-inducing mechanisms of the TIME. CD8 + and CD4 + T cells are enriched in early HCC and progressively decrease during tumour progression.…”

Section: Effector Cellsmentioning

confidence: 99%

“…A recent study suggested the involvement of NKp30 and its ligand B7 homolog 6 (B7‐H6) in HCC development and evolution. B7‐H6 expressed by HCC cells was shown to down‐modulate activating NKp30 and to increase insoluble form in advanced stages …”

Section: Introductionmentioning

confidence: 99%

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Cariani

Missale

2019

Liver International

View full text Add to dashboard Cite

The development of immunotherapy for solid tumours has boosted interest in the contexture of tumour immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumour cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high‐resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response and possibly new therapeutic targets. Here, we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies.

show abstract

Deficient Natural Killer Cell NKp30‐Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma

Abstract: these findings provide evidence in support of a role of NKp30 and its major ligand in HCC development and evolution. This article is protected by copyright. All rights reserved.

Cited by 54 publications

References 48 publications

The tumour microenvironment and immune milieu of cholangiocarcinoma

The tumour microenvironment and immune milieu of cholangiocarcinoma

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches

Immune landscape of hepatocellular carcinoma microenvironment: Implications for prognosis and therapeutic applications

Contact Info

Product

Resources

About