NK Cells, Tumor Cell Transition, and Tumor Progression in Solid Malignancies: New Hints for NK-Based Immunotherapy?

Cantoni, Claudia; Huergo-Zapico, Leticia; Parodi, Monica; Pedrazzi, Marco; Mingari, Maria Cristina; Moretta, Alessandro; Sparatore, Bianca; González, Segundo; Olive, Daniel; Bottino, Cristina; Castriconi, Roberta; Vitale, Massimo

doi:10.1155/2016/4684268

Cited by 75 publications

(63 citation statements)

References 164 publications

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“…NK cells are innate immune-effector cells involved in tumor surveillance (10,53,54); however, the functionality of NK cells is altered in patients with cancer (8,10,54), showing reduced degranulation capability and cytotoxicity. Despite their low numbers in TUMs, the presence of CRC infiltrating NK cells can influence patient outcome (14,(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

Angiogenin and the MMP9‐TIMP2 axis are up‐regulated in proangiogenic, decidual NK‐like cells from patients with colorectal cancer

et al. 2018

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NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56CD16CD9CD49 subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Angiogenin and the MMP9‐TIMP2 axis are up‐regulated in proangiogenic, decidual NK‐like cells from patients with colorectal cancer

et al. 2018

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“…CXCR3 antagonist AMG487 can inhibit metastases in OS murine models, and targeting CXCR3 inhibits metastasis without adversely affecting the host's antitumoral response in breast cancer . However, high natural killer cell infiltration in solid tumors has been reported to be a good prognostic factor, and the recruitment of CXCR3‐positive natural killer cells to the tumor site promotes survival in mouse models of lymphoma and melanoma . Therefore, further studies need to be conducted to better understand the therapeutic effect of targeting CXCR3 in OS.…”

Section: Discussionmentioning

confidence: 99%

“…30 However, high natural killer cell infiltration in solid tumors has been reported to be a good prognostic factor, and the recruitment of CXCR3-positive natural killer cells to the tumor site promotes survival in mouse models of lymphoma and melanoma. 31,32 Therefore, further studies need to be conducted to better understand the therapeutic effect of targeting CXCR3 in OS.…”

Section: Discussionmentioning

confidence: 99%

A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG

Flores

Kelly

et al. 2016

Cancer

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Background Osteosarcoma is the most common malignant pediatric bone tumor. Identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. In this study, we investigated the significance of circulating cytokines/chemokines to predict prognosis at initial diagnosis. Experimental design We employed Luminex assays to measure cytokine/chemokine concentrations from blood samples in a discovery cohort of osteosarcoma patients from Texas Children's Hospital (n= 37) and an independent validation cohort obtained from the Children's Oncology Group (n= 233). Following validation of biomarkers, we constructed a multivariable model to stratify patients into risk groups. Results The circulating concentrations of CXCL10, FLT3LG, IFNG, and CCL4 were significantly associated with overall survival in both cohorts. Of these candidates, CXCL10 and FLT3LG were independent from the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer-versus-control. By combining CXCL10, FLT3LG and metastatic status at diagnosis, we developed a multivariate model that significantly stratified the patients into four distinct risk groups (p = 1.6e-8). Survival analysis showed that 5-year overall survival rates for the “Low”, “Intermediate”, “High” and “Very-high” risk groups were 77%, 54%, 47%, and 10% respectively, while 5-event-free survival rates were 64%, 47%, 27%, and 0% respectively. Neither CXCL10 nor FLT3LG tumor expression were significantly associated with survival. Conclusions High circulating levels of CXCL10 and FLT3LG predicted worse survival in osteosarcoma. Since both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy in osteosarcoma.

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“…Many solid tumors are encapsulated by a dense layer of the ECM that makes it particularly difficult for immune cells to infiltrate. Several studies have shown that NK and other immune cells tend to accumulate in the stroma of the invasive margin rather than invade the tumor core itself (1,2), ultimately limiting effective antitumor immunity (3).…”

Section: Introductionmentioning

confidence: 99%