Metabolic Modulation of the Tumor Microenvironment Leads to Multiple Checkpoint Inhibition and Immune Cell Infiltration
| Autor: | David A. Kolb, Nagesh Kolishetti, Subham Guin, Bapurao Surnar, Shanta Dhar, Shrita Sarkar, Anuj S. Shah |
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| Rok vydání: | 2020 |
| Předmět: |
Tumor microenvironment
Pyruvate dehydrogenase kinase Chemistry Tumor-infiltrating lymphocytes General Engineering General Physics and Astronomy 02 engineering and technology 010402 general chemistry 021001 nanoscience & nanotechnology 01 natural sciences Immune checkpoint 0104 chemical sciences Glycolysis Inhibition Immune system Lymphocytes Tumor-Infiltrating Neoplasms Cancer cell Cancer research Tumor Microenvironment Cytotoxic T cell Humans Nanoparticles General Materials Science 0210 nano-technology Glycolysis |
| Zdroj: | ACS nano. 14(9) |
| ISSN: | 1936-086X |
| Popis: | Cancer cells are known to be glycolytic, driving increased glucose consumption and its conversion to lactate. This process modulates the tumor microenvironment (TME). In the TME, glycolytically activated immune cells often become anergic, leading to an increase in immune checkpoint proteins such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Most glycolytic inhibitors not only inhibit glycolysis of cancer but also of immune cells. Therefore, using a nanoparticle-delivered agent to preferentially inhibit glycolysis in tumor cells, and not in immune cells, has the potential to attenuate the expression of checkpoint proteins. Pyruvate dehydrogenase kinase 1 (PDK1) can be an important target to achieve tumor specific glycolysis inhibition. We report TME modulation by a mitochondrion-targeted nanoparticle (NP) containing a prodrug of dichloroacetate (DCA), a PDK1 inhibitor. We demonstrated that the targeted NP alters the TME which results in increased immunological activation against cancer cells, causing a decrease in mean tumor volume. Here, we also show findings that when Mito-DCA, a prodrug of DCA, was combined with anti-PD-1, a checkpoint inhibitor, results from in vivo syngeneic models showed an upregulation in the number of tumor infiltrating lymphocytes. This work provides a platform to bring therapeutic efficacy by selectively inhibiting glycolysis of cancer cells. |
| Databáze: | OpenAIRE |
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