Antibody-dependent cellular phagocytosis of tropomyosin receptor kinase C (TrkC) expressing cancer cells for targeted immunotherapy
Document Type
Article
Publication Date
9-1-2022
Abstract
Conventional cancer therapies such as chemotherapy are non-selective and induce immune system anergy, which lead to serious side effects and tumor relapse. It is a challenge to prime the body's immune system in the cancer-bearing subject to produce cancer antigen-targeting antibodies, as most tumor-associated antigens are expressed abundantly in cancer cells and some of normal cells. This study illustrates how hapten-based pre-immunization (for anti-hapten antibodies production) combined with cancer receptor labeling with hapten antigen constructs can elicit antibody-dependent cellular phagocytosis (ADCP). Thus, the hapten antigen 2,4-dinitrophenol (DNP) was covalently combined with a cancer receptor-binding dipeptide (IYIY) to form a dipeptide-hapten construct (IYIY-DNP, MW = 1322.33) that targets the tropomyosin receptor kinase C (TrkC)-expressed on the surface of metastatic cancer cells. IYIY-DNP facilitated selective association of RAW264.7 macrophages to the TrkC expressing 4T1 cancer cells in vitro, forming cell aggregates in the presence of anti-DNP antibodies, suggesting initiation of anti-DNP antibody-dependent cancer cell recognition of macrophages by the IYIY-DNP. In in vivo, IYIY-DNP at 10 mg/kg suppressed growth of 4T1 tumors in DNP-immunized BALB/c mice by 45% (p < 0.05), when comparing the area under the tumor growth curve to that of the saline-treated DNP-immunized mice. Meanwhile, IYIY-DNP at 10 mg/kg had no effect on TrkC-negative 67NR tumor-bearing mice immunized with DNP. Tumor growth suppression activity of IYIY-DNP in DNP-immunized mice was associated with an increase in the anti-DNP IgG (7.3 x 10(6) +/- 1.6 U/mL) and IgM (0.9 x 10(6) +/- 0.07 U/mL) antibodies after five cycles of DNP treatment, demonstrated potential for hapten-based pre-immunization then treatment with IYIY-DNP to elicit ADCP for improved immunotherapy of TrkC expressing cancers.
Keywords
Dinitrophenol, Immunotherapy, Antibody-dependent cellular phagocytosis, TrkC, Ligand-hapten conjugate, Active targeting
Divisions
fac_med,pharchemistry
Funders
Ministry of Higher Education Malaysia Fundamental Research Grant Scheme (Grant No: FRGS/1/2020/SKK0/MSU/02/1),National Cancer Council Malaysia (MAKNA) Cancer Research Award (CRA) 2017,United States Department of Health & Human Services National Institutes of Health (NIH) - USA (Grant No: R01EY029645),Texas A&M University T3-Grants Program (Grant No: 246292-00000)
Publication Title
Cancer Immunology Immunotherapy
Volume
71
Issue
9
Publisher
SPRINGER
Publisher Location
ONE NEW YORK PLAZA, SUITE 4600, NEW YORK, NY, UNITED STATES