Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56<sup>bright</sup>CD16<sup>−</sup> cells and display an impaired capability to kill tumor cells

Carrega, Paolo; Morandi, Barbara; Costa, Roberta; Frumento, Guido; Forte, Giuseppe; Altavilla, Giuseppe; Ratto, G. B.; Mingari, Maria Cristina; Moretta, Alessandro; Ferlazzo, Guido

doi:10.1002/cncr.23239

Cited by 332 publications

(326 citation statements)

References 51 publications

(70 reference statements)

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“…Recently, we have described that an endogenously activated pleural fluid NK (PF-NK) population is a major source of IFN-g in response to Mtb [10,11]. Consistently, PF-NK are enriched in CD56 bright cells, as has been observed in other chronic inflammatory sites [12,13] or in tumor-affected tissues [14]. Together with the classical NK functions (i.e.…”

Section: Introductionsupporting

confidence: 54%

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

et al. 2009

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Tuberculous pleurisy, one of the most common manifestations of extrapulmonary tuberculosis, is characterized by a T-cell-mediated hypersensitivity reaction along with a Th1 immune profile. In this study, we investigated functional cross-talk among T and NK cells in human tuberculous pleurisy. We found that endogenously activated pleural fluidderived NK cells express high ICAM-1 levels and induce T-cell activation ex vivo through ICAM-1. Besides, upon in vitro stimulation with monokines and PAMP, resting peripheral blood NK cells increased ICAM-1 expression leading to cellular activation and Th1 polarization of autologous T cells. Furthermore, these effects were abolished by anti-ICAM-1 Ab. Hence, NK cells may contribute to the adaptive immune response by a direct cellcontact-dependent mechanism in the context of Mycobacterium tuberculosis infection.Key words: ICAM-1 . NK cells . Pleurisy . Th1 . Tuberculosis Supporting Information available online IntroductionPleuritis is the most frequent clinical manifestation of extrapulmonary tuberculosis (TB) among young adults, and is normally considered a relatively benign form of disease since it may resolve without chemotherapy [1]. Tuberculous pleurisy is caused by a severe delayed-type hypersensitivity reaction in response to the rupture of a subpleural focus of Mycobacterium tuberculosis (Mtb) infection, but it may also be developed as a complication of primary pulmonary TB [2,3]. This pleural effusion is characterized by a strong granulomatous inflammatory response to Mtb together with high levels of . NK cells are CD56 1 CD16 1/À /CD3 À CD19 À lymphocytes of the innate immune system whose function is controlled by an array of germline-encoded activator/inhibitory receptors [5,6]. Two subsets of NK cells have been identified in humans according to CD56 expression differing in phenotype and function, and also in terms of chemokine receptors and adhesion molecules expression [7,8,9]. Functionally, CD56 bright cells are effective cytokine producers, whereas CD56 dim cells are efficient effectors of natural and Ab-dependent target cell lysis. Recently, we have described that an endogenously activated pleural fluid NK (PF-NK) population is a major source of IFN-g in response to Mtb [10,11]. Consistently, PF-NK are enriched in CD56 bright cells, as has been observed in other chronic inflammatory sites [12,13] or in tumor-affected tissues [14]. Together with the classical NK functions (i.e. cytotoxicity and cytokine production), novel skills have recently been described in niche-specific and in vitro-activated human NK cells. These unconventional capabilities include [16,17,18] and direct pathogen recognition [19,20]. In this regard, a novel innate immune cell population called Interferon-producing killer dendritic cells has been recently described in mice [21,22].ICAM-1/CD54 is the major ligand of costimulatory a L b 2 integrin (CD11a/CD18), commonly known as lymphocyte function-associated antigen (LFA-1) [23,24]. The surface enhancement of ICAM-1 on endothelial, APC and...

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Section: Introductionsupporting

confidence: 54%

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

et al. 2009

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Section: Resultsmentioning

confidence: 98%

“…We have previously shown that a CD3 neg CD56 þ NKp44 þ cell population selectively infiltrates NSCLC, whereas it is virtually undetectable in normal lung tissues 42 . In addition, NCR þ cells are mainly localized in the tumour stroma, in particular within stromal regions characterized by high density of lymphocytes 42 . As NCR þ ILC3 express high levels of NKp44, these data prompted us to further investigate whether the various ILC subsets, and in particular Group 3 ILC expressing NCRs, were present in the tumour microenvironment.…”

Section: Resultsmentioning

confidence: 98%

“…In agreement with this hypothesis we found that the amount of NCR þ ILC3 within tumour infiltrate correlated with the density of intratumoral TLS. Although other lymphocytes of the tumour microenvironment may produce a similar pattern of soluble factors, including LTa/b and TNF-a, which are critical for the possible LTi properties, NCR þ ILC3 may play an exclusive role in the tumour microenvironment: first, they might be directly activated by cancer cells via NKp44 and therefore represent an early innate source of relevant cytokines; then compared with intratumoral NK cells, which may also be directly activated by cancer cells 42,48 , NCR þ ILC3 apparently lack inhibitory receptors controlling their activities and can also provide a unique innate source of IL-2, a crucial growth factor for the clonal expansion of tumour-specific lymphocytes. On the other hand, the role of an innate source of IL-22 within tumour microenvironment remains to be identified and might even favour cancer cell growth 49 .…”

Section: Discussionmentioning

confidence: 99%

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NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

et al. 2015

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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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“…33,34 Similar changes and dysfunction were reported in NK cells isolated from patients with esophageal squamous cell carcinoma and non-small cell lung carcinoma, particularly in pleural effusion. 38,39 The downregulation of CD16 on NK cells has been shown to be driven by TGFβ and leads to conversion from cytotoxic to a more immunoregulatory phenotype similar to decidual NK cells. 30,38 In the current study, we found that NK cells downregulated their CD16 expression upon exposure to ovarian tumor microenvironment but this conversion was mitigated by PD-L1 blockade.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 blockade enhances anti-tumor efficacy of NK cells

2018

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Anti-PD-1/anti-PD-L1 therapies have shown success in cancer treatment but responses are limited to ~ 15% of patients with lymphocyte infiltrated, PD-L1 positive tumors. Hence, strategies that increase PD-L1 expression and tumor infiltration should make more patients eligible for PD-1/PD-L1 blockade therapy, thus improving overall outcomes. PD-L1 expression on tumors is induced by IFNγ, a cytokine secreted by NK cells. Therefore, we tested if PM21-particle expanded NK cells (PM21-NK cells) induced expression of PD-L1 on tumors and if anti-PD-L1 treatment enhanced NK cell anti-tumor efficacy in an ovarian cancer model. Studies here showed that PM21-NK cells secrete high amounts of IFNγ and that adoptively transferred PM21-NK cells induce PD-L1 expression on SKOV-3 cells in vivo. The induction of PD-L1 expression on SKOV-3 cells coincided with the presence of regulatory T cells (Tregs) in the abdominal cavity and within tumors. In in vitro experiments, anti-PD-L1 treatment had no direct effect on cytotoxicity or cytokine secretion by predominantly PD-1 negative PM21-NK cells in response to PD-L1+ targets. However, significant improvement of NK cell anti-tumor efficacy was observed in vivo when combined with anti-PD-L1. PD-L1 blockade also resulted in increased in vivo NK cell persistence and retention of their cytotoxic phenotype. These results support the use of anti-PD-L1 in combination with NK cell therapy regardless of initial tumor PD-L1 status and indicate that NK cell therapy would likely augment the applicability of anti-PD-L1 treatment.

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Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56^brightCD16⁻ cells and display an impaired capability to kill tumor cells

Cited by 332 publications

References 51 publications

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

PD-L1 blockade enhances anti-tumor efficacy of NK cells

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Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56brightCD16− cells and display an impaired capability to kill tumor cells

Cited by 332 publications

References 51 publications

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

NK cells from tuberculous pleurisy express high ICAM‐1 levels and exert stimulatory effect on local T cells

NCR+ILC3 concentrate in human lung cancer and associate with intratumoral lymphoid structures

PD-L1 blockade enhances anti-tumor efficacy of NK cells

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Natural killer cells infiltrating human nonsmall‐cell lung cancer are enriched in CD56^brightCD16⁻ cells and display an impaired capability to kill tumor cells