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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 mice eradicated their primary tumors. The peptibody was capable to deplete notably splenic CD11b+/Gr-1+ cells as well as intratumoral CD11b+/Gr-1+ cells (P < 0.0001) and led to an increased number of tumor infiltrating CD8+ T cells (3.3 folds) and also that of resident tumor draining lymph nodes (TDLNs) (3 folds). Combination of peptibody and 1 T0 mAb resulted in enhanced expansion of tumor infiltrating CD4 + and CD8+ T cells which was associated with tumor eradication in 60 % of the mice. Peptibody is able to deplete CD11b+/Gr-1+ cells and increase anti-tumoral effects of the 1 T0 mAb in tumor eradication. Thus, this myeloid population have critical roles in development of tumors and their depletion is associated with induction of anti-tumoral responses. [ABSTRACT FROM AUTHOR]