Abstract
Targeted cancer immunotherapy is a promising tool for restoring immune surveillance and eradicating cancer cells. Hydrophilic polymers modified with coiled coil peptide tags can be used as universal carriers designed for cell-specific delivery of such biologically active proteins. Here, we describe the preparation of pHPMA-based copolymer conjugated with immunologically active protein B7-H6 via complementary coiled coil VAALEKE (peptide E) and VAALKEK (peptide K) sequences. Receptor B7-H6 was described as a binding partner of NKp30, and its expression has been proven for various tumor cell lines. The binding of B7-H6 to NKp30 activates NK cells and results in Fas ligand or granzyme-mediated apoptosis of target tumor cells. In this work, we optimized the expression of coiled coil tagged B7-H6, its ability to bind activating receptor NKp30 has been confirmed by isothermal titration calorimetry, and the binding stoichiometry of prepared chimeric biopolymer has been characterized by analytical ultracentrifugation. Furthermore, this coiled coil B7-H6-loaded polymer conjugate activates NK cells in vitro and, in combination with coiled coil scFv, enables their targeting towards a model tumor cell line. Prepared chimeric biopolymer represents a promising precursor for targeted cancer immunotherapy by activating the cytotoxic activity of natural killer cells.
Highlights
The immune system is defending our body from external threats and from the harm that may come from the inside in a process called immunosurveillance [1]
As B7-H6 is a single-pass type I membrane protein [31], this arrangement respects its natural structural features, leaving the N-terminal domain containing an interaction interface with the NKp30 receptor unmodified, while C-terminus, which is in the full-length B7-H6 oriented towards cell membrane, contains the coiled coil sequence
Biocompatible pHPMA copolymers loaded with bioactive protein compounds are a promising tool for targeted cancer immunotherapy
Summary
The immune system is defending our body from external threats (e.g., pathogens, toxins) and from the harm that may come from the inside (e.g., malignant growth of transformed cells) in a process called immunosurveillance [1]. As healthy cells undergo malignant transformation, the dynamic mutual communication with immune cells turns into immunoediting [2,3,4]. Despite all efforts of numerous lymphocyte populations, this process is not always leading to tumor suppression, but may instead result in tumor escape [3,5,6] This immune system failure is caused by the tumor’s ability to surround itself with a tumor-suppressing microenvironment [7]. The key cellular players in immunotherapy are cytotoxic effector cells, such as T-cells (as well as their subpopulations NKT lymphocytes, Tc-lymphocytes, or γδT-lymphocytes)
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