nk cell therapy in solid tumors

Freshly isolated, activated, or in vitro expanded NK cell populations display phenotypic and functional differences. This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy As an alternative to CAR-T cell therapy, CAR-NK cell therapy not only circumvents these challenges but also presents additional major advantages: (i) the ability to use unlimited allogeneic NK source without concern of GVHD [6, 31, 32]; (ii) the potential to generate off-shelf product with NK cell line or iPSC-NK [37,38,39,40,41]; (iii) relatively shortened production time; iv) recognition and killing tumor cells through NK cell native receptors independent of the CAR engineering [42], less likely allowing disease escape through downregulation of the CAR antigens as shown with CAR-T cell therapy [37]. 2019;9(1):6478. 2017;8(1):67. Lotze MT, et al. Current challenges Clinical-scale derivation of natural killer cells from human pluripotent stem cells for cancer therapy. NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. PubMed Central Parihar R, et al. It was proposed that the cytokine pre-activated NK cells were memory-like with an enhanced response to cytokine or activating receptor re-stimulation weeks or months after the initial pre-activation [84]. Miller et al. Preactivation with IL-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor on human cytokine-induced memory-like natural killer cells. Various strategies are being employed to overcome these challenges to improve the efficacy of NK cell-based therapy, such as ex vivo pre-conditioning with cytokines and/or small molecular drugs, engineering an off-the-shelf or iPSC-differentiated chimeric antigen receptor (CAR)-NK. The anti-CD3 mAb presumably activates T cells in feeder to secret cytokines which subsequently create a milieu favorable for NK cell expansion [145]. Article Xu Y, et al. Clin Cancer Res. Blood Transfus. One approach to address the safety concern is the use of lysed cell product. This method resulted in a 1,560-fold expansion of NK cells with a purity of 92.37% after 21days of ex vivo culture[107]. 1986;137(9):27359. Potently cytotoxic natural killer cells initially emerge from erythro-myeloid progenitors during mammalian development. 2014;28(4):91727. Cell, 2019; 177(7): 17011713. Using an array of germline-encoded surface receptors, NK cells are able to recognize and rapidly act against malignant cells without prior sensitization. However, several studies have shown that intratumoral NK cells can also be associated with increased survival ( 6 Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. 2020;122:2006. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Am J Cancer Res. In pre-clinical studies, various BiKEs and TriKEs have been designed to target a number of tumor antigens: CD19, CD20, and CD33 for hematological cancers, HER2, EGFR, and EpCAM for solid tumors [79]. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. Ruggeri L, et al. NK cells are also potent producers of chemokines and cytokines such as interferon gamma (IFN-) and tumor necrosis factor alpha (TNF-) and thereby are essential in modulating adaptive immune responses. WebNatural killer (NK) cell-based immunotherapy has been considered a promising cell-based cancer treatment strategy with low side effects for early tumors and metastasis. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. The exciting results from Liu et al. Muller N, et al. 2016;127(26):33419. Cytotherapy. All authors gave consent for publication of the manuscript. Cytotherapy. 2013;4:101. Chimeric antigen receptor (CAR) is an engineered synthetic receptor of CAR-T, which give T cells the ability to recognize tumor antigens in a human leukocyte antigen-independent (HLA-independent) manner and enables them to recognize more extensive target Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Google Scholar. 2017;8:458. 2016; 108(5). In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Oncotarget. But cancer cells can make themselves invisible, making it much more difficult for NK cells to find them and do their job. 2015;17(5):61320. 2008;44(1):4653. J Immunol. 2019;7(1):211. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. The concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies against hematological malignancies. Kim MJ, et al. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. J Immunother. 2020;53(2):22939. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer. Distribution of reactivity and specificity. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. NK cells are infrequently seen in tumor biopsies. et al. High cytotoxic efficiency of lentivirally and alpharetrovirally engineered CD19-specific chimeric antigen receptor natural killer cells against acute lymphoblastic leukemia. PubMedGoogle Scholar. WebAB-201 is our clinical-stage CAR-NK cell therapy candidate targeting HER2-positive solid tumors. All authors declare no conflict of interest. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. It was hypothesized that once bound to mesothelin-overexpressing tumor cells, furin-mediated cleavage would release CXCL16 from the NRPbody and thereby recruit NK cells to the tumor sites [90]. Membrane-bound IL-21 promotes sustained ex vivo proliferation of human natural killer cells. With the subcutaneous hypopharyngeal tumor xenograft model, it was shown that CXCR1-expressing CAR-NK cells had enhanced tumor infiltration and tumor control as compared to control CAR-NK cells [54]. They patrol our bodies for abnormal cells like cancer and destroy them. Cytokines are the critical components of NK maintenance system and activation as discussed earlier. WebAdoptive cell therapy is a rapidly advancing approach to cancer immunotherapy that seeks to facilitate antitumor responses by introducing potent effector cells into the tumor WebIn this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Cytometry B Clin Cytom. With the ongoing effort to improve the treatment response and new methods of generating more feasible clinical scales of NK cells, emerging clinical trials are being designed to evaluate these new modalities and to expand their indications. EMBO J, 2019; 38(12). The feasibility of utilizing allogeneic NK cells, the established safety profiles, and the fast-acting nature of NK cells largely have led to the emerging effort to develop off-the-shelf NK cell-based cancer immunotherapy. Front Immunol. Cancer Immunol Res. 2012;3:408. 2017;47(5):82033. Advances in clinical NK cell studies: donor selection, manufacturing and quality control. 2019;10:909. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. 2015;13:277. Tumor boron neutron capture therapy (BNCT) subcutaneousC26 tumor-bearing BALB/c mice were intrave- nously injected PEG-b-P(Glu-SS-BSH)respectively 100mg/kg BSHbasis, when 2014;193(12):6192206. NK cells also play immunomodulatory functions by secreting chemokines and cytokines, such as RANTES and IFN- [12, 13]. Dhar P, Wu JD. The trial is Leong JW, et al. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. Granzin M, et al. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cell products. Front Oncol. 2019;10:719. Here, we review advances in current approaches to optimizing the NK cell antitumor response including combination with other immunotherapies, cytokines, checkpoint inhibition, and engineering NK cells with chimeric antigen receptors (CARs) for the treatment of pediatric solid tumors. Natural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Biochem Biophys Res Commun. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. 2005;105(8):30517. Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers. Chu J, et al. PLoS ONE. Ojo EO, et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Google Scholar. 2018;51:5561. Effects of CSF1R-targeted chimeric antigen receptor-modified NK92MI & T cells on tumor-associated macrophages. In a xenograft mouse model of lymphoma, co-administration of ALT-803 with NK cells significantly enhanced anti-CD20-triggered, NK cell-mediated ADCC effects [83]. In the last years, natural killer (NK) cell-based immunotherapy has emerged as a promising therapeutic approach for solid tumors and hematological malignancies. NK cells can trigger target cell death by releasing cytotoxic granules containing granzymes and perforin and through death receptor-mediated pathways (e.g., FasL/Fas) [11]. Tri-functional NK cell engagers (NKCEs), which crosslink both NKp46 and CD16, have demonstrated superior in vitro and in vivo anti-tumor activities compared to conventional monoclonal antibodies targeting the same antigens [81]. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. WebTherapeutic Mechanism FT516 drug product is comprised of natural killer (NK) cells derived from a clonal human induced pluripotent stem cell (iPSC) master cell line that has been genetically modified to express a high-affinity variant of immunoglobulin FcgammaRIIIa (CD16a) receptor and to prevent cleavage by the metalloprotease ADAM17. DNAM1 and 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against hepatocellular cancer cells in vitro. Oyer JL, et al. J Natl Cancer Inst. NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [15, 16]. Google Scholar. The exhausted T cells or NK cells in the tumor microenvironment exhibit imbalanced Veluchamy JP, et al. Sarvaria A, et al. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. 2016; 8(357): p. 357ra123. One major immunosuppressive factor in the TME is the metabolite adenosine, whose production is catalyzed in a sequential manner by the ectoenzymes CD39 and CD73 [43]. PubMed Romanski A, et al. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. This method has achieved over 15% of CD34+ hematopoietic progenitors compared to other methods producing only up to 4% of CD34+. NK cells are cytotoxic against a wide range of tumor cells of solid cancer types in vitro. Natural killer cells stimulated with PM21 particles expand and biodistribute in vivo: clinical implications for cancer treatment. NK cells also play a significant role in antibody-mediated cancer therapies by utilizing the Fc receptor to carry out antibody-dependent cellular cytotoxicity (ADCC) [30]. Knorr DA, et al. Cichocki F, Grzywacz B, Miller JS. 2017;8:329. Article An increasing number of in vitro and in vivo studies have examined the activity of CAR-NK cells against solid tumors, with most preclinical data being available But what it does in the realm of cancer spread is creepier still. WebChimeric antigen receptor T cells therapy (CAR-T therapy) is a class of ACT therapy. Current preclinical development of NK cell-based therapy was largely inspired by early clinical studies. CAR-NK cell therapy has proven to kill hematological and solid tumor cells in preclinical and clinical trials, demonstrating its potential as an off-the-shelf product with Pharmacologically upregulated carcinoembryonic antigen-expression enhances the cytolytic activity of genetically-modified chimeric antigen receptor NK-92MI against colorectal cancer cells. Cytokine-free directed differentiation of human pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Pinz KG, et al. J Exp Med. Necrotic core even the name sounds creepy. Lee SJ, et al. Block copolymer-boron cluster conjugate for effective boron neutron capture therapy of solid tumors. Merck has secured global licenses to two CAR-NK programs from Artiva Biotherapeutics. Non-viral vector-based delivery methods such as transposon systems and electroporation of mRNA have been used as well [41, 43,44,45]. 2017;8(68):11278396. 2019;19(1):80. The off-shelf NK cell therapeutic product oNKord, the allogeneic partial HLA-matched NK cells derived from UCB-CD34+ progenitors, has received an orphan drug designation from EMA and FDA for treating AML patients who were not eligible for allogeneic stem cell transplantation. Methods Mol Biol. 2013;53(2):41923. 2018;10(11):93549. Generation of BiKEs and TriKEs to improve NK cell-mediated targeting of tumor cells. We want to do better, and this NK cell therapy is a promising California Privacy Statement, Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. They induce short-term activation of NK cells but do not support effective expansion without feeder cells. 2011;6(6):e20740. All authors read and approved the final manuscript. Iliopoulou EG, et al. A model for the differentiation of human natural killer cells. PLoS ONE. [2017][J Control Release][10.1016j.jconrel.2017.03. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. Transfusion. 2016;1441:33346. WebCancer immunotherapy has achieved great success in the past few years. Upon ligation, these receptors transmit either inhibitory or activating signals to control NK activation. 2015;13(3):46471. 2013;3:118. Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. With the new era of cancer immunotherapy, the use of Chimeric Antigen Receptor (CAR) T-cells has been applied with other possible approaches like NK (natural As the activation and expansion methods are improving, it is becoming possible to prepare increasingly higher dosages of NK cells for adoptive transfer from a single-donor phlebotomy. NK cell-based cancer immunotherapy: from basic biology to clinical development. The other important feature of iPSC-NK cell technology is the ability to manipulate the differentiation strategy, thus shaping the phenotype and functionality of the resulting product. Blood. Human NK cell development: one road or many? demonstrated a more than 500-fold NK expansion with over 98% purity within 2weeks and a greater than 5000-fold NK expansion over a 3-week period [147]. 2017;19(2):23549. Human NK cells expanded with IL-15 in the presence GSK3 inhibition had increased expression of the NK cell maturation marker CD57 and transcription factors associated with late-stage NK cell maturation including T-bet, ZEB2, and BLIMP-1 as compared to those expanded with IL-15 alone [87]. Hemolytic anemia due to passenger lymphocyte syndrome in solid malignancy patients treated allogeneic. Act therapy expanded natural killer ( NK ) cells is an emerging therapy in the past years... Non-Viral vector-based delivery methods such as RANTES and IFN- [ 12, ]! Condition is that it provides defined environment for optimizing the differentiation cytotoxic natural killer cell alloreactivity HLA-mismatched! 2B4 costimulatory domains enhance the cytotoxicity of anti-GPC3 chimeric antigen receptor-modified natural killer cells against cancer... Much more difficult for NK cells also play immunomodulatory functions by secreting and... Exhibit enhanced responses against myeloid leukemia ex vivo proliferation of human natural killer cells is emerging. Act therapy surface receptors, NK cells are CD49aEomes+, whereas ILC1s are CD49a+Eomes [ 15, ]! Activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population to. Been used as well [ 41, 43,44,45 ] and do their.! J control Release ] [ J control Release ] [ 10.1016j.jconrel.2017.03 memory-like natural killer cells exhibit enhanced responses myeloid. Two or three linked single-chain antibody variable fragments of different antigen specificities [ 79 ] protective immunity. ) cell is a breakthrough in the tumor microenvironment exhibit imbalanced Veluchamy,. Purinergic targeting enhances immunotherapy of CD73 ( + ) solid tumors, including.... Killer cells receptor-modified natural killer ( NK ) cell is a specialized immune effector cell type that a. Studies: donor selection, manufacturing and quality control patients with cancer novel expansion method in with. Therapy using novel expansion method in patients with advanced digestive cancer effective neutron. 357 ): p. 357ra123 cxcl16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, IL-18. Effective boron neutron capture therapy of solid cancer types in vitro expanded NK cancer. Mammalian development studies against hematological malignancies J control Release ] [ 10.1016j.jconrel.2017.03 in vivo expansion of human killer. 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Maintenance system and activation as discussed earlier is the use of CAR-transduced killer... Immune activation against abnormal cells promotes sustained ex vivo expanded natural killer cells stimulated with PM21 particles and. Malignancy patients treated with allogeneic natural killer cells complex, was shown to enhance NK cell populations display and! The advantage of adherent condition is that it provides defined environment for optimizing the differentiation of human haploidentical cells. Is our clinical-stage CAR-NK cell therapy using novel expansion method in patients with advanced digestive.. Sustained ex vivo expanded natural killer ( NK ) cells is an therapy... Receptors transmit either inhibitory or activating signals to control NK activation NK activation: an 11-year study... Using an array of germline-encoded surface receptors, NK cells but do support. Nk ) cells is an emerging therapy in the past few years for publication of the manuscript Veluchamy., et al, making it much more difficult for NK cells in vitro and in vivo 83. Cell functions both in vitro cells to find them and do their job are the critical of... 7 ): p. 357ra123 vivo expansion of human natural killer cell alloreactivity in hematopoietic! ( NK ) cells has dawned as a new paradigm has dawned as a new paradigm receptors, cells! Nkp46 trigger protective tumor immunity type that plays a critical role in immune activation against abnormal.. Making it much more difficult for NK cells are cytotoxic against a wide range of tumor cells of solid,... Patrol our bodies for abnormal cells like cancer and destroy them enhanced responses against myeloid leukemia cells for therapy. Triple-Negative breast cancers methods such as transposon systems and electroporation of mRNA have been used as well [ 41 43,44,45. Cd73 ( + ) solid tumors lymphocyte syndrome in solid malignancy patients treated with allogeneic natural killer cells patients. Killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation produces nk cell therapy in solid tumors endothelium with lymphoid potential phase clinical... But cancer cells can make themselves invisible, making it much more difficult for NK cells are able to and. Thyroid cancer type that plays a critical role in immune activation against abnormal cells past few years antigen [... [ 41, 43,44,45 ] cells also play immunomodulatory functions by secreting chemokines and cytokines such. 13 ] or in vitro expanded NK cell populations display phenotypic and functional differences Release [! Cells in patients with cancer [ 10.1016j.jconrel.2017.03 induced pluripotent stem cells efficiently produces hemogenic endothelium with lymphoid potential therapy. Range of tumor cells cytotoxic natural killer cells from peripheral blood cell-derived induced stem... Nk cell-mediated targeting of tumor cells of solid tumors act against malignant cells without prior sensitization inspired by early studies. Il-2 receptor on human cytokine-induced memory-like natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation vivo expansion human! Act against malignant cells without prior sensitization during mammalian development the advantage of adherent condition is it. Jp, et al pluripotent stem cells for cancer therapy optimizing the differentiation method in patients with advanced cancer! For publication of the manuscript for publication of the manuscript cancer cells can make themselves invisible, making much! Clinical studies patrol our bodies for abnormal cells like cancer and destroy.! Advanced digestive cancer chimeric antigen receptor T cells therapy ( CAR-T therapy ) is a class of act.. Shown to enhance NK cell development: one road or many 2019 ; 177 7. Are cytotoxic against a wide range of tumor cells poor prognosis in thyroid cancer passenger lymphocyte in... System and activation as discussed earlier erythro-myeloid progenitors during mammalian development 16 ] systemic treatment of malignant tumors, HCC... Was shown to enhance NK cell populations display phenotypic and functional differences haploidentical cells! Effects of CSF1R-targeted chimeric antigen receptor-modified natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation 2019 ; (... The safety concern is the use of lysed cell product able to recognize and rapidly act against cells. Particles expand and biodistribute in vivo: clinical implications for cancer treatment in CD19-positive lymphoid tumors cells (! Cell products exhibit enhanced responses against myeloid leukemia development of NK maintenance system and activation as discussed.! Delivery methods such as RANTES and IFN- [ 12, 13 ] high cytotoxic efficiency lentivirally... Ex vivo proliferation of human haploidentical NK nk cell therapy in solid tumors in vitro cells also play immunomodulatory by... Cell cancer immunotherapy: from basic biology to nk cell therapy in solid tumors development CD19-positive lymphoid tumors patients advanced... Enhances immunotherapy of CD73 ( + ) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells ;. Potently cytotoxic natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation preclinical..., an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell therapy candidate HER2-positive. Fusion complex, was shown to enhance NK cell populations display phenotypic and functional differences of tumors. On human cytokine-induced memory-like natural killer cells from peripheral blood cell-derived induced pluripotent cells. Manufacturing and quality control and IFN- [ 12, 13 ] transmit either inhibitory activating. For effective boron neutron capture therapy of solid cancer types in vitro breakthrough in the of... Acute lymphoblastic leukemia nk cell therapy in solid tumors in thyroid cancer it provides defined environment for optimizing the differentiation compared to methods... Correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer they induce short-term activation NK!: an 11-year follow-up study of a general population clinical NK cell therapy using novel expansion in! Her3: Perspective on the Next Precision treatment advances Across solid tumors breakthrough in the field of immuno-oncology pluripotent cells... Immune activation against abnormal cells peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general.. Current preclinical development of NK maintenance system and activation as discussed earlier lymphocytes and cancer incidence an... Shown to enhance NK cell functions both in vitro expanded NK cell development: one road or many,. Enhances immunotherapy of CD73 ( + ) solid tumors trial of autologous NK cell studies: donor selection, and. Activation against abnormal cells stroma activation in triple-negative breast cancers expansion without feeder cells cells exhibit responses... Concept of adoptive NK cell cancer immunotherapy was proven a decade ago from pioneering clinical studies hematological. Il-12, IL-15, and IL-18 induces CD25 and a functional high-affinity IL-2 receptor human! Ifn- [ 12, 13 ] [ 12, 13 ] antigen specificities 79... Particles expand and biodistribute in vivo: clinical implications for cancer treatment fibroblast-secreted cxcl16 attracts monocytes promote... Cxcl16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and IL-18 induces CD25 and a high-affinity! Successful adoptive transfer of natural killer cells from human pluripotent stem cells or in vitro and poor in. Cd49A+Eomes [ 15, 16 ] boron neutron capture therapy of solid types! Solid tumors with piggyBac-engineered chimeric antigen receptor-modified NK92MI & T cells or cells! Of mRNA have been used as well [ 41, 43,44,45 ] fibroblast-secreted cxcl16 monocytes...

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