A microparticle platform for STING-targeted immunotherapy enhances natural killer cell- and CD8+ T cell-mediated anti-tumor immunity

Biomaterials. 2019 Jun:205:94-105. doi: 10.1016/j.biomaterials.2019.03.011. Epub 2019 Mar 14.

Abstract

Immunotherapies have significantly improved cancer patient survival, but response rates are still limited. Thus, novel formulations are needed to expand the breadth of immunotherapies. Pathogen associated molecular patterns (PAMPs) can be used to stimulate an immune response, but several pathogen recognition receptors are located within the cell, making delivery challenging. We have employed the biodegradable polymer acetalated dextran (Ace-DEX) to formulate PAMP microparticles (MPs) in order to enhance intracellular delivery. While treatment with four different PAMP MPs resulted in tumor growth inhibition, cyclic GMP-AMP (cGAMP) MPs were most effective. cGAMP MPs showed anti-tumor efficacy at doses 100-1000 fold lower than published doses of soluble cGAMP in two murine tumor models. Treatment with cGAMP MPs resulted in increased natural killer cell numbers in the tumor environment. Immune cell depletion studies confirmed that NK cells were responsible for the anti-tumor efficacy in an aggressive mouse melanoma model. NK cells and CD8+ T cells were both required for early anti-tumor function in a triple negative breast cancer model. In summary, cGAMP MP treatment results in NK and T cell-dependent anti-tumor immune response.

Keywords: Acetalated dextran; CD8(+) T cells; Immunotherapy; Microparticle; Natural killer cells; STING.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Dextrans / chemistry
  • Disease Models, Animal
  • Hydrodynamics
  • Immunity*
  • Immunotherapy*
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Melanoma / immunology
  • Melanoma / pathology
  • Melanoma / therapy
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Microspheres*
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Nucleotides, Cyclic / pharmacology
  • Pathogen-Associated Molecular Pattern Molecules / metabolism
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy
  • Tumor Burden / drug effects

Substances

  • Dextrans
  • Membrane Proteins
  • Nucleotides, Cyclic
  • Pathogen-Associated Molecular Pattern Molecules
  • STING1 protein, human
  • cyclic guanosine monophosphate-adenosine monophosphate