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Type 2 innate lymphoid cells (ILC2s) are crucial in regulating immune responses and various physiological processes, including tissue repair, metabolic homeostasis, inflammation, and cancer surveillance. Here, we present a protocol that outlines the isolation, expansion, and adoptive transfer of human ILC2s from peripheral blood mononuclear cells for an in vivo lineage tracking experiment in a mouse model. Additionally, we detail the steps involved in the adoptive transfer of human ILC2s to recipient mice bearing human liquid or solid tumors. For complete details on the use and execution of this protocol, please refer to Li et al.1.
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Limited therapeutic options are available for patients with breast cancer brain metastases (BCBM), and thus there is an urgent need for novel treatment approaches. We previously engineered an effective oncolytic herpes simplex virus 1 (oHSV) expressing a full-length anti-CD47 monoclonal antibody (mAb) with a human IgG1 scaffold (OV-αCD47-G1) that was used to treat both ovarian cancer and glioblastoma. Here, we demonstrate that the combination of OV-αCD47-G1 and temozolomide (TMZ) improve outcomes in preclinical models of BCBM. The combination of TMZ with OV-αCD47-G1 synergistically increased macrophage phagocytosis against breast tumor cells and led to greater activation of NK cell cytotoxicity. In addition, the combination of OV-αCD47-G1 with TMZ significantly prolonged the survival of tumor-bearing mice when compared with TMZ or OV-αCD47-G1 alone. Combination treatment with the mouse counterpart of OV-αCD47-G1, termed OV-A4-IgG2b, also enhanced mouse macrophage phagocytosis, NK cell cytotoxicity, and survival in an immunocompetent model of mice bearing BCBM compared with TMZ or OV-A4-IgG2b alone. Collectively, these results suggest that OV-αCD47-G1 combined with TMZ should be explored in patients with BCBM.
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Tumors evade attacks from the immune system through various mechanisms. Here, we identify a component of tumor immune evasion mediated by YTH domain-containing family protein 2 (YTHDF2), a reader protein that usually destabilizes m6A-modified mRNA. Loss of tumoral YTHDF2 inhibits tumor growth and prolongs survival in immunocompetent tumor models. Mechanistically, tumoral YTHDF2 deficiency promotes the recruitment of macrophages via CX3CL1 and enhances mitochondrial respiration of CD8+ T cells by impairing tumor glycolysis metabolism. Tumoral YTHDF2 deficiency promotes inflammatory macrophage polarization and antigen presentation in the presence of IFN-γ. In addition, IFN-γ induces autophagic degradation of tumoral YTHDF2, thereby sensitizing tumor cells to CD8+ T cell-mediated cytotoxicity. Last, we identified a small molecule compound that preferentially induces YTHDF2 degradation, which shows a potent antitumor effect alone but a better effect when combined with anti-PD-L1 or anti-PD-1 antibodies. Collectively, YTHDF2 appears to be a tumor-intrinsic regulator that orchestrates immune evasion, representing a promising target for enhancing cancer immunotherapy.
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Ratones Endogámicos C57BL , Proteínas de Unión al ARN , Animales , Proteínas de Unión al ARN/inmunología , Proteínas de Unión al ARN/genética , Ratones , Humanos , Evasión Inmune , Escape del Tumor/inmunología , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/genética , Línea Celular Tumoral , Linfocitos T CD8-positivos/inmunología , FemeninoRESUMEN
We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18, and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared with non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared with NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).
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Antígeno B7-H1 , Carcinoma de Pulmón de Células no Pequeñas , Interleucina-15 , Células Asesinas Naturales , Neoplasias Pulmonares , Ensayos Antitumor por Modelo de Xenoinjerto , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Animales , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Antígeno B7-H1/metabolismo , Ratones , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Línea Celular Tumoral , Ratones SCID , Ratones Endogámicos NOD , FemeninoRESUMEN
Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.
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Antígenos de Neoplasias , Proteínas Ligadas a GPI , Células Madre Pluripotentes Inducidas , Macrófagos , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/inmunología , Animales , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Proteínas Ligadas a GPI/metabolismo , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Proteínas de Neoplasias/metabolismo , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Inmunoterapia Adoptiva/métodos , Ratones SCIDRESUMEN
The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.
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Granzimas , Inmunidad Innata , Linfocitos , Neoplasias , Animales , Humanos , Ratones , Apoptosis , Citocinas , Neoplasias/inmunología , Neoplasias/terapiaRESUMEN
The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid ß-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.
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Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide de Fase Crónica , Leucemia Mieloide , MicroARNs , Animales , Humanos , Ratones , Crisis Blástica , Células MadreRESUMEN
Lung cancer is the leading cause of cancer-related death worldwide. Although natural killer (NK) cells are garnering interest as a potential anticancer therapy because they selectively recognize and eliminate cancer cells, their use in treating solid tumors, including lung cancer, has been limited due to impediments to their efficacy, such as their limited ability to reach tumor tissues, the reduced antitumor activity of tumor-infiltrating NK cells, and the suppressive tumor microenvironment (TME). This comprehensive review provides an in-depth analysis of the cross-talk between the lung cancer TME and NK cells. We highlight the various mechanisms used by the TME to modulate NK-cell phenotypes and limit infiltration, explore the role of the TME in limiting the antitumor activity of NK cells, and discuss the current challenges and obstacles that hinder the success of NK-cell-based immunotherapy for lung cancer. Potential opportunities and promising strategies to address these challenges have been implemented or are being developed to optimize NK-cell-based immunotherapy for lung cancer. Through critical evaluation of existing literature and emerging trends, this review provides a comprehensive outlook on the future of NK-cell-based immunotherapy for treating lung cancer.
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The majority of patients with acute myeloid leukemia (AML) succumb to the disease or its complications, especially among older patients. Natural killer (NK) cells have been shown to have antileukemic activity in patients with AML; however, to our knowledge, primary NK cells armed with a chimeric antigen receptor (CAR) targeting antigens associated with AML as an "off-the-shelf" product for disease control have not been explored. We developed frozen, off-the-shelf allogeneic human NK cells engineered with a CAR recognizing FLT3 and secreting soluble interleukin-15 (IL-15) (FLT3 CAR_sIL-15 NK) to improve in vivo NK cell persistence and T-cell activation. FLT3 CAR_sIL-15 NK cells had higher cytotoxicity and interferon gamma secretion against FLT3+ AML cell lines when compared with activated NK cells lacking an FLT3 CAR or soluble IL-15. Frozen and thawed allogeneic FLT3 CAR_sIL-15 NK cells prolonged survival of both the MOLM-13 AML model as well as an orthotopic patient-derived xenograft AML model when compared with control NK cells. FLT3 CAR_sIL-15 NK cells showed no cytotoxicity against healthy blood mononuclear cells or hematopoietic stem cells. Collectively, our data suggest that FLT3 is an AML-associated antigen that can be targeted by frozen, allogeneic, off-the-shelf FLT3 CAR_sIL-15 NK cells that may provide a novel approach for the treatment of AML.
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Leucemia Mieloide Aguda , Receptores Quiméricos de Antígenos , Humanos , Receptores Quiméricos de Antígenos/metabolismo , Interleucina-15/farmacología , Interleucina-15/metabolismo , Células Asesinas Naturales , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Epstein-Barr virus (EBV) is a ubiquitous herpes virus associated with various cancers. EBV establishes latency with life-long persistence in memory B-cells and can reactivate lytic infection placing immunocompromised individuals at risk for EBV-driven lymphoproliferative disorders (EBV-LPD). Despite the ubiquity of EBV, only a small percentage of immunocompromised patients (~20%) develop EBV-LPD. Engraftment of immunodeficient mice with peripheral blood mononuclear cells (PBMCs) from healthy EBV-seropositive donors leads to spontaneous, malignant, human B-cell EBV-LPD. Only about 20% of EBV+ donors induce EBV-LPD in 100% of engrafted mice (High-Incidence, HI), while another 20% of donors never generate EBV-LPD (No-Incidence, NI). Here, we report HI donors to have significantly higher basal T follicular helper (Tfh) and regulatory T-cells (Treg), and depletion of these subsets prevents/delays EBV-LPD. Transcriptomic analysis of CD4+ T cells from ex vivo HI donor PBMC revealed amplified cytokine and inflammatory gene signatures. HI vs. NI donors showed a marked reduction in IFNγ production to EBV latent and lytic antigen stimulation. In addition, we observed abundant myeloid-derived suppressor cells in HI donor PBMC that decreased CTL proliferation in co-cultures with autologous EBV+ lymphoblasts. Our findings identify potential biomarkers that may identify individuals at risk for EBV-LPD and suggest possible strategies for prevention.
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BACKGROUND: Type I interferons (IFN-Is), secreted by hematopoietic cells, drive immune surveillance of solid tumors. However, the mechanisms of suppression of IFN-I-driven immune responses in hematopoietic malignancies including B-cell acute lymphoblastic leukemia (B-ALL) are unknown. METHODS: Using high-dimensional cytometry, we delineate the defects in IFN-I production and IFN-I-driven immune responses in high-grade primary human and mouse B-ALLs. We develop natural killer (NK) cells as therapies to counter the intrinsic suppression of IFN-I production in B-ALL. RESULTS: We find that high expression of IFN-I signaling genes predicts favorable clinical outcome in patients with B-ALL, underscoring the importance of the IFN-I pathway in this malignancy. We show that human and mouse B-ALL microenvironments harbor an intrinsic defect in paracrine (plasmacytoid dendritic cell) and/or autocrine (B-cell) IFN-I production and IFN-I-driven immune responses. Reduced IFN-I production is sufficient for suppressing the immune system and promoting leukemia development in mice prone to MYC-driven B-ALL. Among anti-leukemia immune subsets, suppression of IFN-I production most markedly lowers the transcription of IL-15 and reduces NK-cell number and effector maturation in B-ALL microenvironments. Adoptive transfer of healthy NK cells significantly prolongs survival of overt ALL-bearing transgenic mice. Administration of IFN-Is to B-ALL-prone mice reduces leukemia progression and increases the frequencies of total NK and NK-cell effectors in circulation. Ex vivo treatment of malignant and non-malignant immune cells in primary mouse B-ALL microenvironments with IFN-Is fully restores proximal IFN-I signaling and partially restores IL-15 production. In B-ALL patients, the suppression of IL-15 is the most severe in difficult-to-treat subtypes with MYC overexpression. MYC overexpression promotes sensitivity of B-ALL to NK cell-mediated killing. To counter the suppressed IFN-I-induced IL-15 production in MYChigh human B-ALL, we CRISPRa-engineered a novel human NK-cell line that secretes IL-15. CRISPRa IL-15-secreting human NK cells kill high-grade human B-ALL in vitro and block leukemia progression in vivo more effectively than NK cells that do not produce IL-15. CONCLUSION: We find that restoration of the intrinsically suppressed IFN-I production in B-ALL underlies the therapeutic efficacy of IL-15-producing NK cells and that such NK cells represent an attractive therapeutic solution for the problem of drugging MYC in high-grade B-ALL.
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Linfoma de Burkitt , Interferón Tipo I , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ratones , Animales , Interferón gamma/metabolismo , Interleucina-15/metabolismo , Células Asesinas Naturales , Linfoma de Burkitt/patología , Ratones Transgénicos , Interferón Tipo I/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Microambiente TumoralRESUMEN
Serine proteases (SP), including furin, trypsin, and TMPRSS2 cleave the SARS-CoV-2 spike (S) protein, enabling the virus to enter cells. Here, we show that factor (F) Xa, an SP involved in blood coagulation, is upregulated in COVID-19 patients. In contrast to other SPs, FXa exerts antiviral activity. Mechanistically, FXa cleaves S protein, preventing its binding to ACE2, and thus blocking viral entry and infection. However, FXa is less effective against variants carrying the D614G mutation common in all pandemic variants. The anticoagulant rivaroxaban, a direct FXa inhibitor, inhibits FXa-mediated S protein cleavage and facilitates viral entry, whereas the indirect FXa inhibitor fondaparinux does not. In the lethal SARS-CoV-2 K18-hACE2 model, FXa prolongs survival yet its combination with rivaroxaban but not fondaparinux abrogates that protection. These results identify both a previously unknown function for FXa and an associated antiviral host defense mechanism against SARS-CoV-2 and suggest caution in considering direct FXa inhibitors for preventing or treating thrombotic complications in COVID-19 patients.
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COVID-19 , Factor Xa , Humanos , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Rivaroxabán/farmacología , Rivaroxabán/uso terapéutico , SARS-CoV-2/metabolismo , Internalización del Virus , Antivirales/farmacologíaRESUMEN
Spliced X-box-binding protein 1 (XBP1s) is an essential transcription factor downstream of interleukin-15 (IL-15) and AKT signaling, which controls cell survival and effector functions of human natural killer (NK) cells. However, the precise mechanisms, especially the downstream targets of XBP1s, remain unknown. In this study, by using XBP1 conditional knockout mice, we found that XBP1s is critical for IL-15-mediated NK cell survival but not proliferation in vitro and in vivo. Mechanistically, XBP1s regulates homeostatic NK cell survival by targeting PIM-2, a critical anti-apoptotic gene, which in turn stabilizes XBP1s protein by phosphorylating it at Thr58. In addition, XBP1s enhances the effector functions and antitumor immunity of NK cells by recruiting T-bet to the promoter region of Ifng. Collectively, our findings identify a previously unknown mechanism by which IL-15-XBP1s signaling regulates the survival and effector functions of NK cells.
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Interleucina-15 , Proteínas Serina-Treonina Quinasas , Proteína 1 de Unión a la X-Box , Animales , Humanos , Ratones , Proteínas de Unión al ADN/genética , Retroalimentación , Células Asesinas Naturales/metabolismo , Ratones Noqueados , Factores de Transcripción/genética , Proteína 1 de Unión a la X-Box/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
When we can understand what natural killer (NK) cells recognize during an encounter with an infectious pathogen or a tumor cell, and when we can understand how the NK cell responds to that encounter, we can then begin to understand the role of NK cells in human health and how to improve upon their role for the prevention and treatment of human disease. In the quest to understand how these cells function in antiviral and antitumoral immunity, there have been previously described mechanisms established for NK cells to participate in clearing viral infections and tumors, including classical NK cell antibody dependent cellular cytotoxicity (ADCC) as well as recognition and elimination of transformed malignant cells through direct ligand interactions. However, it is now clear that there are additional mechanisms by which NK cells can participate in these critical immune tasks. Here we review two recently described types of NK cell recognition and response: the first is to primary infection with herpes virus, recognized and responded to by non-specific Fc bridged cellular cytotoxicity (FcBCC), and the second describes a novel phenotypic and functional response when a subset of NK cells recognize myeloid leukemia.
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Células Asesinas Naturales , Neoplasias , Humanos , Citotoxicidad Celular Dependiente de Anticuerpos , Neoplasias/terapia , Neoplasias/patología , AntiviralesRESUMEN
BACKGROUND: Mammalian cells have developed multiple intracellular mechanisms to defend against viral infections. These include RNA-activated protein kinase (PKR), cyclic GMP-AMP synthase and stimulation of interferon genes (cGAS-STING) and toll-like receptor-myeloid differentiation primary response 88 (TLR-MyD88). Among these, we identified that PKR presents the most formidable barrier to oncolytic herpes simplex virus (oHSV) replication in vitro. METHODS: To elucidate the impact of PKR on host responses to oncolytic therapy, we generated a novel oncolytic virus (oHSV-shPKR) which disables tumor intrinsic PKR signaling in infected tumor cells. RESULTS: As anticipated, oHSV-shPKR resulted in suppression of innate antiviral immunity and improves virus spread and tumor cell lysis both in vitro and in vivo. Single cell RNA sequencing combined with cell-cell communication analysis uncovered a strong correlation between PKR activation and transforming growth factor beta (TGF-ß) immune suppressive signaling in both human and preclinical models. Using a murine PKR targeting oHSV, we found that in immune-competent mice this virus could rewire the tumor immune microenvironment to increase the activation of antigen presentation and enhance tumor antigen-specific CD8 T cell expansion and activity. Further, a single intratumoral injection of oHSV-shPKR significantly improved the survival of mice bearing orthotopic glioblastoma. To our knowledge, this is the first report to identify dual and opposing roles of PKR wherein PKR activates antivirus innate immunity and induces TGF-ß signaling to inhibit antitumor adaptive immune responses. CONCLUSIONS: Thus, PKR represents the Achilles heel of oHSV therapy, restricting both viral replication and antitumor immunity, and an oncolytic virus that can target this pathway significantly improves response to virotherapy.
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Neoplasias Encefálicas , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Humanos , Ratones , Neoplasias Encefálicas/patología , Viroterapia Oncolítica/métodos , Simplexvirus , Factor de Crecimiento Transformador beta , Microambiente Tumoral , eIF-2 Quinasa/metabolismoRESUMEN
Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+ T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ-STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10-STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Macrófagos , Macrófagos Asociados a Tumores , Neoplasias/metabolismo , Inmunoterapia , Microambiente Tumoral , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismoRESUMEN
Oncolytic viruses (OVs) provide novel and promising therapeutic options for patients with cancers resistant to traditional therapies. Natural or genetically modified OVs are multifaceted tumor killers. They directly lyse tumor cells while sparing normal cells, and indirectly potentiate antitumor immunity by releasing antigens and activating inflammatory responses in the tumor microenvironment. However, some limitations, such as limited penetration of OVs into tumors, short persistence, and the host antiviral immune response, are impeding the broad translation of oncolytic virotherapy into the clinic. If these challenges can be overcome, combination therapies, such as OVs plus immune checkpoint blockade (ICB), chimeric antigen receptor (CAR) T cells, or CAR natural killer (NK) cells, may provide powerful therapeutic platforms in the clinic.
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Neoplasias , Viroterapia Oncolítica , Virus Oncolíticos , Humanos , Virus Oncolíticos/genética , Inmunoterapia , Neoplasias/terapia , Células Asesinas Naturales , Microambiente TumoralRESUMEN
Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR+ glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors.
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Neoplasias Encefálicas , Glioblastoma , Herpesvirus Humano 1 , Viroterapia Oncolítica , Virus Oncolíticos , Animales , Ratones , Inmunidad Adaptativa , Neoplasias Encefálicas/terapia , Cetuximab/farmacología , Receptores ErbB/genética , Glioblastoma/genética , Virus Oncolíticos/genética , Microambiente Tumoral , Quimiocina CCL5/metabolismoRESUMEN
Natural killer (NK) cells, a crucial component of the innate immune system, have long been of clinical interest for their antitumor properties. Almost every aspect of NK cell immunity is regulated by interleukin-15 (IL-15), a cytokine in the common γ-chain family. Several current clinical trials are using IL-15 or its analogs to treat various cancers. Moreover, NK cells are being genetically modified to produce membrane-bound or secretory IL-15. Here, we discuss the key role of IL-15 signaling in NK cell immunity and provide an up-to-date overview of IL-15 in NK cell therapy.