Evaluation of the anti-tumor effects of an anti-Human Epidermal growth factor receptor 2 (HER2) monoclonal antibody in combination with CD11b+/Gr-1+ myeloid cells depletion using a recombinant peptibody in 4 T1-HER2 tumor model

• Published in: International immunopharmacology 2023-08, Vol.121, p.110463-110463, Article 110463
• Main Authors: Ramezani-Aliakbari, Khadijeh, Khaki-Bakhtiarvand, Vahid, Mahmoudian, Jafar, Asgarian-Omran, Hossein, Shokri, Fazel, Hojjat-Farsangi, Mohammad, Jeddi-Tehrani, Mahmood, Shabani, Mahdi
• Format: Article
• Language: English
• Subjects: 1T0 mAb; Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Agents - pharmacology; Cancer immunotherapy; CD11b Antigen; CD11b+/Gr-1+ cell; CD8-Positive T-Lymphocytes; Cell Line, Tumor; HER2; Humans; Medicin och hälsovetenskap; Mice; Mice, Inbred BALB C; Myeloid Cells; Neoplasms; Peptibody; Tumor microenvironment
• ISSN: 1567-5769; 1878-1705; 1878-1705
• DOI: 10.1016/j.intimp.2023.110463

A) anti-HER2 mAb therapy leads to release tumor Ags from dying cells responding to immunomodulation. anti-HER2 mAbs have directly cytotoxic effects on tumor cells via ADCC, ADPC, CDC involving NK cells, macrophages and complement cascade, respectively. Then, tumor debris can complex with anti-HER2 mAbs and these immune complexes following with FC/FCR interaction facilitate cross presentation of tumor antigens by resident DCs. Tumor specific T lymphocytes are activated in peripheral lymphoid organs by the mature DCs. Effector T cells can migrate to tumor bed through blood circulation and lead to lysis of tumor cells. B) Combination anti-HER2 mAb with treatment of CD11b+/Gr1+ MDSCs depleting peptibody can overcome tumor induced immunoregulatory signals and associated to eradication of established tumors by infiltrating effector T cells. CD11b+/Gr1+ myeloid cells notably impair function of effector innate and adoptive immune cells in tumor microenvironment and limit anti-tumor efficacy of tumor targeting mAbs in vivo. So, co-targeting HER2 tumor antigen and CD11b+/Gr1+ myeloid cells in a combinatory strategy may overcome on this obstacle and restore anti-tumor responses mediating the tumor elimination. [Display omitted] •Peptibody significantly depletes the tumor induced CD11b+/Gr1+ MDSCs in 4 T1-HER2 murine model.•Peptibody treatment leads to eradication or regression of tumors in 4 T1-HER2 model.•CD11b+/Gr1+ myeloid cells reduction by peptibody restores the cell mediated anti-tumor responses.•CD11b+/Gr1+ myeloid cells targeting can improve clinical outcomes of immunotherapeutic approaches. Clinical efficacy of Human Epidermal growth factor Receptor 2 (HER2) targeted strategies is limited due to impaired anti-tumor responses negatively regulated by immunosuppressive cells. We thus, investigated the inhibitory effects of an anti-HER2 monoclonal antibody (1 T0 mAb) in combination with CD11b+/Gr-1+ myeloid cells depletion in 4 T1-HER2 tumor model. BALB/c mice were challenged with human HER2-expressing 4 T1 murine breast cancer cell line. A week post tumor challenge, each mouse received 50 µg of a myeloid cells specific peptibody every other day, or 10 mg/kg of 1 T0 mAb two times a week, and their combination for two weeks. The treatments effect on tumor growth was measured by calculating tumor size. Also, the frequencies of CD11b+/Gr-1+ cells and T lymphocytes were measured by flow cytometry. Peptibody treated mice indicated tumor regression and 40 % of the mic