Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

Kisseberth, William C.; Lee, Dean A.

doi:10.3389/fvets.2021.672361

Cited by 8 publications

(9 citation statements)

References 70 publications

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“…To overcome these negative effects and induce resistance of NK cells to TGF-β, Kisseberth et al. ( 110 ) continuously exposed NK cells to low-dose TGF-β and IL2 in vitro , thereby alleviating the degree of immunosuppression in the canine osteosarcoma microenvironment, which might be applied to the treatment of human NK cells in the future.…”

Section: Cellsmentioning

confidence: 99%

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications

et al. 2022

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Osteosarcoma is a primary malignant tumor that tends to threaten children and adolescents, and the 5-year event-free survival rate has not improved significantly in the past three decades, bringing grief and economic burden to patients and society. To date, the genetic background and oncogenesis mechanisms of osteosarcoma remain unclear, impeding further research. The tumor immune microenvironment has become a recent research hot spot, providing novel but valuable insight into tumor heterogeneity and multifaceted mechanisms of tumor progression and metastasis. However, the immune microenvironment in osteosarcoma has been vigorously discussed, and the landscape of immune and non-immune component infiltration has been intensively investigated. Here, we summarize the current knowledge of the classification, features, and functions of the main infiltrating cells, complement system, and exosomes in the osteosarcoma immune microenvironment. In each section, we also highlight the complex crosstalk network among them and the corresponding potential therapeutic strategies and clinical applications to deepen our understanding of osteosarcoma and provide a reference for imminent effective therapies with reduced adverse effects.

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Section: Cellsmentioning

confidence: 99%

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications

et al. 2022

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“…The study of ADCC in rodent syngeneic tumor models is limited by species differences in immune cell effector functions, including significant differences in human and mouse CD16 expression and function (see Introduction). The dog spontaneous cancer model incorporates heterogeneous disease and an intact immune system with many similarities to humans to help determine the mechanisms that underlie success and failure of immunotherapies (24)(25)(26). We have extended the current understanding of the dog immune system by demonstrating phenotypic and functional characteristics of canine CD16A and CD64 to advance utilizing these FcgRs for therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

“…Canine NK cells are phenotypically distinguished based on their lack of B cell markers, CD3, CD4, and TCRs ( 24 , 25 ). CD5 bright lymphocytes in the dog have been classified as T cell ( 24 ); however, there are conflicting views on CD5 expression by canine NK cells, which have been reported as CD5 +/− and CD5 dim ( 27 , 30 , 38 ).…”

Section: Discussionmentioning

confidence: 99%

“…An ideal animal model for understanding the mechanisms that underlie success and failure of human immunotherapies should incorporate heterogeneous spontaneous disease and an intact immune system that is similar to humans. A comparable incidence of human and certain canine malignancies, combined with their shared biologic and pathologic characteristics, and similar response to therapy indicate that dogs can provide a clinically relevant disease model (24)(25)(26).…”

Section: Introductionmentioning

confidence: 93%

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Examination of IgG Fc Receptor CD16A and CD64 Expression by Canine Leukocytes and Their ADCC Activity in Engineered NK Cells

Hullsiek

Snyder

et al. 2022

Front. Immunol.

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Human natural killer (NK) cells can target tumor cells in an antigen-specific manner by the recognition of cell bound antibodies. This process induces antibody-dependent cell-mediated cytotoxicity (ADCC) and is exclusively mediated by the low affinity IgG Fc receptor CD16A (FcγRIIIA). Exploiting ADCC by NK cells is a major area of emphasis for advancing cancer immunotherapies. CD64 (FcγRI) is the only high affinity IgG FcR and it binds to the same IgG isotypes as CD16A, but it is not expressed by human NK cells. We have generated engineered human NK cells expressing recombinant CD64 with the goal of increasing their ADCC potency. Preclinical testing of this approach is essential for establishing efficacy and safety of the engineered NK cells. The dog provides particular advantages as a model, which includes spontaneous development of cancer in the setting of an intact and outbred immune system. To advance this immunotherapy model, we cloned canine CD16A and CD64 and generated specific mAbs. We report here for the first time the expression patterns of these FcγRs on dog peripheral blood leukocytes. CD64 was expressed by neutrophils and monocytes, but not lymphocytes, while canine CD16A was expressed at high levels by a subset of monocytes and lymphocytes. These expression patterns are similar to that of human leukocytes. Based on phenotypic characteristics, the CD16A+ lymphocytes consisted of T cells (CD3+ CD8+ CD5dim α/β TCR+) and NK cells (CD3− CD5− CD94+), but not B cells. Interestingly, the majority of canine CD16A+ lymphocytes were from the T cell population. Like human CD16A, canine CD16A was downregulated by a disintegrin and metalloproteinase 17 (ADAM17) upon leukocyte activation, revealing a conserved means of regulation. We also directly demonstrate that both canine CD16A and CD64 can induce ADCC when expressed in the NK cell line NK-92. These findings pave the way to engineering canine NK cells or T cells with high affinity recombinant canine CD64 to maximize ADCC and to test their safety and efficacy to benefit both humans and dogs.

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“…One mechanism by which tumors continue to grow in the presence of NK cells may be through overexpression of TGF-β, a potent inhibitor of NK cells. Canine OSA tumors consistently stain positive for TGFβRI and TGFβRII ( 61 ), providing a rational for the expansion and transfer of expanded and TGF-β-imprinted NK cells in cOSA therapy ( 62 , 63 ). Imprinting of NK cells involves prolonged coculture with IL-2 and TGF-β to produce NK cells that are desensitized to the inhibitory effects of TGF-β and thereby capable of prolonged hyperfunctionality with increased cytotoxicity, cytokine production, and longevity.…”

Section: Nk Cellsmentioning

confidence: 99%

Natural Killer and T Cell Infiltration in Canine Osteosarcoma: Clinical Implications and Translational Relevance

et al. 2021

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Metastatic osteosarcoma has a bleak prognosis in both humans and dogs, and there have been minimal therapeutic advances in recent decades to improve outcomes. Naturally occurring osteosarcoma in dogs is shown to be a highly suitable model for human osteosarcoma, and limited data suggest the similarities between species extend into immune responses to cancer. Studies show that immune infiltrates in canine osteosarcoma resemble those of human osteosarcoma, and the analysis of tumor immune constituents as predictors of therapeutic response is a promising direction for future research. Additionally, clinical studies in dogs have piloted the use of NK transfer to treat osteosarcoma and can serve as valuable precursors to clinical trials in humans. Cytotoxic lymphocytes in dogs and humans with osteosarcoma have increased activation and exhaustion markers within tumors compared with blood. Accordingly, NK and T cells have complex interactions among cancer cells and other immune cells, which can lead to changes in pathways that work both for and against the tumor. Studies focused on NK and T cell interactions within the tumor microenvironment can open the door to targeted therapies, such as checkpoint inhibitors. Specifically, PD-1/PD-L1 checkpoint expression is conserved across tumors in both species, but further characterization of PD-L1 in canine osteosarcoma is needed to assess its prognostic significance compared with humans. Ultimately, a comparative understanding of T and NK cells in the osteosarcoma tumor microenvironment in both dogs and humans can be a platform for translational studies that improve outcomes in both dogs and humans with this frequently aggressive disease.

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Adoptive Natural Killer Cell Immunotherapy for Canine Osteosarcoma

Cited by 8 publications

References 70 publications

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications

Immune Microenvironment in Osteosarcoma: Components, Therapeutic Strategies and Clinical Applications

Examination of IgG Fc Receptor CD16A and CD64 Expression by Canine Leukocytes and Their ADCC Activity in Engineered NK Cells

Natural Killer and T Cell Infiltration in Canine Osteosarcoma: Clinical Implications and Translational Relevance

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