scholarly journals Platelet-Mediated Protection of Cancer Cells From Immune Surveillance – Possible Implications for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Laurent Schmied ◽  
Petter Höglund ◽  
Stephan Meinke
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Solid Tumor ◽  
Tumor Metastasis ◽  
Nk Cell ◽  
High Exposure ◽  
Hematological Cancers ◽  
The Impact

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

2020 ◽  
Vol 9 (1) ◽  
pp. 143 ◽  
Author(s):  
Cinzia Fionda ◽  
Helena Stabile ◽  
Cristina Cerboni ◽  
Alessandra Soriani ◽  
Angela Gismondi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cancer Cells ◽  
Nk Cell ◽  
Critical Role ◽  
Cell Activity ◽  
Lymphoid Cells ◽  
Receptor Expression ◽  
Nk Cell Activity ◽  
Group I

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

scholarly journals NK Cells in the Treatment of Hematological Malignancies

2019 ◽  
Vol 8 (10) ◽  
pp. 1557 ◽  
Author(s):  
Gonzalez-Rodriguez ◽  
Villa-Álvarez ◽  
Sordo-Bahamonde ◽  
Lorenzo-Herrero ◽  
Gonzalez
Keyword(s):  
Antitumor Activity ◽  
Nk Cells ◽  
Cancer Cells ◽  
Nk Cell ◽  
Hematologic Malignancies ◽  
Therapeutic Approaches ◽  
Hematopoietic Stem ◽  
Checkpoint Proteins ◽  
Hematological Cancers ◽  
Dependent Cell

: Natural killer (NK) cells have the innate ability to kill cancer cells, however, tumor cells may acquire the capability of evading the immune response, thereby leading to malignancies. Restoring or potentiation of this natural antitumor activity of NK cells has become a relevant therapeutic approach in cancer and, particularly, in hematological cancers. The use of tumor-specific antibodies that promote antibody-dependent cell-mediated cytotoxicity (ADCC) through the ligation of CD16 receptor on NK cells has become standard for many hematologic malignancies. Hematopoietic stem cell transplantation is another key therapeutic strategy that harnesses the alloreactivity of NK cells against cancer cells. This strategy may be refined by adoptive transfer of NK cells that may be previously expanded, activated, or redirected (chimeric antigen receptor (CAR)-NK cells) against cancer cells. The antitumor activity of NK cells can also be boosted by cytokines or immunostimulatory drugs such as lenalidomide or pomalidomide. Finally, targeting immunosubversive mechanisms developed by hematological cancers and, in particular, using antibodies that block NK cell inhibitory receptors and checkpoint proteins are novel promising therapeutic approaches in these malignant diseases.

scholarly journals 772 A potent and off-the-shelf oNK cell therapy product targets HER2+ cancer cells and resists suppressive tumor microenvironment

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A821-A821
Author(s):  
Hao-Kang Li ◽  
Ching-Wen Hsiao ◽  
Sen-Han Yang ◽  
Hsiu-Ping Yang ◽  
Tai-Sheng Wu ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Membrane Proteins ◽  
Cell Therapy ◽  
Nk Cells ◽  
Cancer Cells ◽  
Cell Line ◽  
Nk Cell ◽  
Binding Specificity ◽  
Cell Therapy Product

BackgroundAutologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACC) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with trastuzumab, and assess its potency against HER2+ solid tumors.Methods oNK cells were covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACC) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Function of ACE1702 was validated by real-time xCELLigence analyzer and MTT assay in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Characterization of ACE1702 was analyzed by flow cytometry.ResultsWe demonstrated that the trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with different grade of HER2 expressions compared to control oNK cells in vitro. In vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model further supported the in vitro observations. Of note, ACE1702 also displayed a better cytotoxicity against HER2+ cancer cells than trastuzumab and its derived antibody-drug conjugate. ACE1702 also remained cytotoxicity against cancer cells in the suppressive tumor microenvironment. Characterization revealed a preferential expression of NK activation receptors, and conjugation of trastuzumab with cell membrane proteins responsible for NK activity capacitated ACE1702 with enhanced cytotoxicity. These results underscore the potency of ACE1702 in eradication of cancer cells.ConclusionsHere we introduced a novel trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers. Selective conjugation of trastuzumab with membrane proteins contributing to NK activation conferred ACE1702 with enhanced cytotoxicity even in the suppressive tumor microenvironment.AcknowledgementsNoneTrial RegistrationNoneEthics ApprovalThe animal study was conducted according to protocols approved by the Institutional Animal Care and Use Committee of Muragenics.ConsentNone

scholarly journals Genetic Engineering of Natural Killer Cells for Enhanced Antitumor Function

2020 ◽  
Vol 11 ◽  
Author(s):  
Simone Mantesso ◽  
Dirk Geerts ◽  
Jan Spanholtz ◽  
Lucia Kučerová
Keyword(s):  
Tumor Microenvironment ◽  
Genetic Engineering ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Nk Cell ◽  
Induced Response ◽  
Cell Therapies ◽  
Anti Tumor Activity ◽  
Cell Effector

Natural Killer (NK) cells are unique immune cells capable of efficient killing of infected and transformed cells. Indeed, NK cell-based therapies induced response against hematological malignancies in the absence of adverse toxicity in clinical trials. Nevertheless, adoptive NK cell therapies are reported to have exhibited poor outcome against many solid tumors. This can be mainly attributed to limited infiltration of NK cells into solid tumors, downregulation of target antigens on the tumor cells, or suppression by the chemokines and secreted factors present within the tumor microenvironment. Several methods for genetic engineering of NK cells were established and consistently improved over the last decade, leading to the generation of novel NK cell products with enhanced anti-tumor activity and improved tumor homing. New generations of engineered NK cells are developed to better target refractory tumors and/or to overcome inhibitory tumor microenvironment. This review summarizes recent improvements in approaches to NK cell genetic engineering and strategies implemented to enhance NK cell effector functions.

scholarly journals The Impact of the Tumor Microenvironment on Macrophage Polarization in Cancer Metastatic Progression

2021 ◽  
Vol 22 (12) ◽  
pp. 6560
Author(s):  
Huogang Wang ◽  
Mingo M. H. Yung ◽  
Hextan Y. S. Ngan ◽  
Karen K. L. Chan ◽  
David W. Chan
Keyword(s):  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Tumor Metastasis ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Macrophage Polarization ◽  
Interleukin 10 ◽  
The Body ◽  
Metastatic Progression ◽  
The Impact

Rather than primary solid tumors, metastasis is one of the hallmarks of most cancer deaths. Metastasis is a multistage event in which cancer cells escape from the primary tumor survive in the circulation and disseminate to distant sites. According to Stephen Paget's “Seed and Soil” hypothesis, metastatic capacity is determined not only by the internal oncogenic driving force but also by the external environment of tumor cells. Throughout the body, macrophages are required for maintaining tissue homeostasis, even in the tumor milieu. To fulfill these multiple functions, macrophages are polarized from the inflammation status (M1-like) to anti-inflammation status (M2-like) to maintain the balance between inflammation and regeneration. However, tumor cell-enforced tumor-associated macrophages (TAMs) (a high M2/M1 ratio status) are associated with poor prognosis for most solid tumors, such as ovarian cancer. In fact, clinical evidence has verified that TAMs, representing up to 50% of the tumor mass, exert both protumor and immunosuppressive effects in promoting tumor metastasis through secretion of interleukin 10 (IL10), transforming growth factor β (TGFβ), and VEGF, expression of PD-1 and consumption of arginine to inhibit T cell anti-tumor function. However, the underlying molecular mechanisms by which the tumor microenvironment favors reprogramming of macrophages to TAMs to establish a premetastatic niche remain controversial. In this review, we examine the latest investigations of TAMs during tumor development, the microenvironmental factors involved in macrophage polarization, and the mechanisms of TAM-mediated tumor metastasis. We hope to dissect the critical roles of TAMs in tumor metastasis, and the potential applications of TAM-targeted therapeutic strategies in cancer treatment are discussed.

scholarly journals Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL

Cancers ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 277 ◽  
Author(s):  
Kim Clar ◽  
Clemens Hinterleitner ◽  
Pascal Schneider ◽  
Helmut Salih ◽  
Stefanie Maurer
Keyword(s):  
Nk Cells ◽  
Cancer Cells ◽  
Solid Tumors ◽  
Nk Cell ◽  
Disease Free Survival ◽  
Neutralizing Antibody ◽  
Functional Explanation ◽  
Tumor Immune Evasion ◽  
Surface Receptors ◽  
Tumor Immunosurveillance

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors.

scholarly journals Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood

2021 ◽  
Vol 118 (11) ◽  
pp. e2016580118
Author(s):  
Demi Brownlie ◽  
Marlena Scharenberg ◽  
Jeff E. Mold ◽  
Joanna Hård ◽  
Eliisa Kekäläinen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Human Lung ◽  
Nk Cell ◽  
Cell Tumor ◽  
Target Cells ◽  
Suitable Alternative ◽  
Peripheral Tissues ◽  
Hematological Cancers ◽  
Tumor Homing

Human adaptive-like “memory” CD56dimCD16+ natural killer (NK) cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue residency and tumor homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56brightCD16− NK cells with hallmarks of tissue residency, including expression of CD49a. Expansions of adaptive-like lung tissue-resident NK (trNK) cells were found to be present independently of adaptive-like CD56dimCD16+ NK cells and to be hyperresponsive toward target cells. Together, our data demonstrate that phenotypically, functionally, and developmentally distinct subsets of adaptive-like NK cells exist in human lung and blood. Given their tissue-related character and hyperresponsiveness, human lung adaptive-like trNK cells might represent a suitable alternative for therapies targeting solid tumors.

scholarly journals Expansions of adaptive-like NK cells with a tissue-resident phenotype in human lung and blood

2019 ◽  
Author(s):  
Nicole Marquardt ◽  
Marlena Scharenberg ◽  
Jeffrey E. Mold ◽  
Joanna Hård ◽  
Eliisa Kekäläinen ◽  
...  
Keyword(s):  
Nk Cells ◽  
Solid Tumors ◽  
Human Lung ◽  
Nk Cell ◽  
Cell Tumor ◽  
Target Cells ◽  
Suitable Alternative ◽  
Peripheral Tissues ◽  
Hematological Cancers ◽  
Tumor Homing

AbstractHuman adaptive-like “memory” CD56dimCD16+ NK cells in peripheral blood from cytomegalovirus-seropositive individuals have been extensively investigated in recent years and are currently explored as a treatment strategy for hematological cancers. However, treatment of solid tumors remains limited due to insufficient NK cell tumor infiltration, and it is unknown whether large expansions of adaptive-like NK cells that are equipped for tissue-residency and tumor-homing exist in peripheral tissues. Here, we show that human lung and blood contains adaptive-like CD56brightCD16− NK cells with hallmarks of tissue-residency, including expression of CD49a. Expansions of adaptive-like lung tissue-resident (tr)NK cells were found to be present independently of adaptive-like CD56dimCD16+ NK cells and to be hyperresponsive towards target cells. Together, our data demonstrate that phenotypically, functionally, and developmentally distinct subsets of adaptive-like NK cells exist in human lung and blood. Given their tissue-related character and hyperresponsiveness, human lung adaptive-like trNK cells might represent a suitable alternative for therapies targeting solid tumors.

163 Nice: neoantigen-cytokine-chemokine multifunctional engager for NK cell immunotherapy of solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A176-A176
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Solid Tumors ◽  
Immune Cells ◽  
Nk Cell ◽  
Wilms Tumor ◽  
Killer Cell ◽  
Immunosuppressive Tumor Microenvironment

BackgroundThe effectiveness of natural killer cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment. To improve the clinical efficacy and specificity of NK cell therapy, we are designing, developing, and characterizing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains.MethodsTargeting a neoantigen-an antigen formed specifically in response to tumor genome mutations-enables substantially enhanced tumor specificity to be achieved. We evaluated the responsiveness of NK cells to Wilms Tumor 1 (WT1) antigen in GBM by synthesizing an antibody that is able to recognize the WT1/HLA complex. Incorporation of cytokine (namely IL-2, IL-15, and IL-21)-essential for the maturation, persistence, and expansion of NK cells in vivo-favors the proliferation and survival of NK cells in the tumor microenvironment, thereby leading to more sustained anti-tumor responses. Additionally, our data have indicated that the chemokine CXCL10 plays an important role in the infiltration of immune cells into GBM, yet the chemokine itself is expressed at low levels in GBM. Incorporation of a CXCL10-producing element into our construct further supports NK cell recruitment and may stimulate the recruitment of other immune cells. NK activation through the tri-specific engager is achieved through NKp46-mediated signaling. We are investigating the ability of the tri-functional engager to support and enhance NK cell-mediated cytotoxicity against GBM in vitro and in patient-derived GBM xenografts in vivo.ResultsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit, at once, superior persistence, infiltration and antitumor activity, simultaneously addressing three of the main limitations to the use of NK cells in immunotherapy of GBM and other solid tumors.ConclusionsN/AAcknowledgementsN/A

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