To overcome short half-life and immunogenicity, Cao et al. encapsulated lactate oxidase in a thin polymer shell to create proteolytically stable nanocapsules (n(LOx)). In the TME, n(LOx) reduced lactate concentrations and generated H2O2. In a murine melanoma model and a humanized mouse model of triple-negative breast cancer, intratumoral injection of n(LOx) enhanced anti-PD-L1 activity, reduced the Treg cell population, increased proinflammatory cytokine production by TEFF cells, and promoted T cell infiltration into the TME. n(LOx) also exhibited abscopal effects, suppressing the growth of secondary tumors in the alternate flank.
Contributed by Paula Hochman
ABSTRACT: Cancer immunotherapy has reshaped the landscape of cancer treatment. However, its efficacy is still limited by tumor immunosuppression associated with the excessive production of lactate by cancer cells. Although extensive efforts have been made to reduce lactate concentrations through inhibition of lactate dehydrogenase, such inhibitors disrupt the metabolism of healthy cells, causing severe nonspecific toxicity. We report herein a nanocapsule enzyme therapeutic based on lactate oxidase, which reduces lactate concentrations and releases immunostimulatory hydrogen peroxide, averting tumor immunosuppression and improving the efficacy of immune checkpoint blockade treatment. As demonstrated in a murine melanoma model and a humanized mouse model of triple-negative breast cancer, this enzyme therapeutic affords an effective tool toward more effective cancer immunotherapy.
Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. UCLA AIDS Institute, University of California Los Angeles
Author Info: (1) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. (2) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. (3) UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA. (4) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. (5) Division of Nanomedicine, Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA. (6) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA. (7) UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA. (8) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. (9) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. (10) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. (11) UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA. (12) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA. (13) Department of Chemical and Biomolecular Engineering, University of California Los Angeles, Los Angeles, CA 90095, USA. Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China. Changping Laboratory, Beijing 100871, China. (14) UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA 90095, USA. Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
