Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

Raneros, Aroa Baragaño; Suárez-Álvarez, Beatriz; López‐Larrea, Carlos

doi:10.4161/onci.28497

Cited by 72 publications

(61 citation statements)

References 76 publications

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“…In the last decade, the releasing of soluble NKG2D ligands has been extensively investigated with regard to their contribution to tumor pathologies and associated with a worse prognosis among cancer patients. 45 This corollary could be responsible for a premature interaction of soluble tumor-derived ligands with various NCRs resulting in a receptor internalization and abrogated cytotoxicity mediated by various effector cell subsets. 46 Previously, a bi-national NK cell Phase I/II study (Clin-GovNo-NCT01386619) demonstrated the safety, feasibility, and tolerability of using allogeneic un-stimulated and IL-2-activated NK cells in patients with multiple relapsed leukemia and highly malignant solid tumors after receiving HSCT.…”

Section: E1055993-10mentioning

confidence: 99%

Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

et al. 2015

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Abbreviations: ADCC, antigen-dependent cellular cytotoxicity; HNSCC, head-and-neck squamous cell carcinoma; HSCT, haploidentical stem cell transplantation; KIR, killer cell immunoglobulin-like receptor; NCR, natural cytotoxicity receptor; NK, natural killer; NKG2D, natural-killer group 2, member D; vitsMICA/NKG2DL, soluble major histocompatibility complex Class I chain-related peptide A; TGFb1, transforming growth factor beta 1; TIEM, tumor immune escape mechanismDisseminated head-and-neck squamous cell carcinoma (HNSCC) escapes immune surveillance and thus frequently manifests as fatal disease. Here, we report on the distribution of distinct immune cell subpopulations, natural killer (NK) cell cytotoxicity and tumor immune escape mechanisms (TIEMs) in 55 HNSCC patients, either at initial diagnosis or present with tumor relapse. Compared to healthy controls, the regulatory NK cells and the ratio of pro/antiinflammatory cytokines were decreased in HNSCC patients, while soluble major histocompatibility complex Class I chain-related peptide A (sMICA) and transforming growth factor b 1 (TGFb 1 ) plasma levels were markedly elevated. Increased sMICA and TGFb 1 concentrations correlated with tumor progression and staging characteristics in 7 follow-up HNSCC patients, with significantly elevated levels of both soluble factors from the time of initial diagnosis to that of relapse. Patient plasma containing elevated sMICA and TGFb 1 markedly impaired NKG2D-dependent cytotoxicity against HNSCC cells upon incubation with patient-derived and IL-2 activated NK cells vs. those derived from healthy donors. Decreased antitumor recognition was accompanied by reduced NKG2D expression on the NK cell surface and an enhanced caspase-3 activity. In-vitro blocking and neutralization experiments demonstrated a synergistic negative impact of sMICA and TGFb 1 on NK cell functionality. Although we previously showed the feasibility and safety of transfer of allogeneic donor NK cells in a prior clinical study encompassing various leukemia and tumor patients, our present results suggest the need for caution regarding the sole use of adoptive NK cell transfer. The presence of soluble NKG2D ligands in the plasma of HNSCC patients and the decreased NK cell cytotoxicity due to several factors, especially TGFb 1 , indicates timely depletion of these immunosuppressing molecules may promote NK cell-based immunotherapy.

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Section: E1055993-10mentioning

confidence: 99%

Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

et al. 2015

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“…Indeed, soluble forms of NKG2DLs are present in the serum of cancer patients, and their levels correlate with tumor stage and metastasis (12,20,21,(38)(39)(40)(41), as well as with reduced expression of NKG2D on NK cells and other cytotoxic lymphocytes (11,21,42).…”

Section: Discussionmentioning

confidence: 99%

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

Zingoni

Cecere

Vulpis

et al. 2015

The Journal of Immunology

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Genotoxic stress can promote antitumor NK cell responses by upregulating the surface expression of activating ligands on cancer cells. Moreover, a number of studies suggested a role for soluble NK group 2D ligands in the impairment of NK cell tumor recognition and killing. We investigated whether genotoxic stress could promote the release of NK group 2D ligands (MHC class I-related chain [MIC]A and MICB), as well as the molecular mechanisms underlying this event in human multiple myeloma (MM) cells. Our results show that genotoxic agents used in the therapy of MM (i.e., doxorubicin and melphalan) selectively affect the shedding of MIC molecules that are sensitive to proteolytic cleavage, whereas the release of the short MICA*008 allele, which is frequent in the white population, is not perturbed. In addition, we found that a disintegrin and metalloproteinase 10 expression is upregulated upon chemotherapeutic treatment both in patient-derived CD138(+)/CD38(+) plasma cells and in several MM cell lines, and we demonstrate a crucial role for this sheddase in the proteolytic cleavage of MIC by means of silencing and pharmacological inhibition. Interestingly, the drug-induced upregulation of a disintegrin and metalloproteinase 10 on MM cells is associated with a senescent phenotype and requires generation of reactive oxygen species. Moreover, the combined use of chemotherapeutic drugs and metalloproteinase inhibitors enhances NK cell-mediated recognition of MM cells, preserving MIC molecules on the cell surface and suggesting that targeting of metalloproteinases in conjunction with chemotherapy could be exploited for NK cell-based immunotherapeutic approaches, thus contributing to avoid the escape of malignant cells from stress-elicited immune responses

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“…A more complete understanding of NK and sNKG2DL function in LAM pathogenesis could lead to development of NK-based interventional targets and perhaps inform treatment decisions in the future. Clinical trials that target NKG2DLs (58)(59)(60) in other neoplastic diseases are underway and may reveal strategies that could be successfully applied to LAM. Table 1).…”

Section: Discussionmentioning

confidence: 99%

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline

et al. 2016

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Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

Cited by 72 publications

References 76 publications

Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline

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Secretory pathways generating immunosuppressive NKG2D ligands: New targets for therapeutic intervention

Cited by 72 publications

References 76 publications

Increased sMICA and TGFβ 1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Increased sMICA and TGFβ 1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Genotoxic Stress Induces Senescence-Associated ADAM10-Dependent Release of NKG2D MIC Ligands in Multiple Myeloma Cells

NK cell activating receptor ligand expression in lymphangioleiomyomatosis is associated with lung function decline

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Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Increased sMICA and TGFβ ₁ levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells