Background: Humanized mice engrafted with tumors enable in vivo investigation of the interactions between the human immune system and human cancer. We have recently found that humanized NOD-scid IL2Rγ^null(NSG) mice bearing patient-derived xenografts (PDX) allow efficacy studies of check-point inhibitors. Next generation NSG strains include triple transgenic NSG mice expressing human cytokines KITLG, CSF2, and IL-3 (NSG-SGM3). Methods: We provide a direct comparison of check-point inhibitors evaluation in NSG and NSG-SGM3 mice engrafted with CD34⁺ human hematopoietic progenitor cells (HPCs) from the same donor and implanted with PDX tumors. PDX tumors were engrafted into partially HLA-matched hu-NSG-SGM3 mice at 9 weeks post engraftment. Tumor-infiltrating myeloid cells were examined. Two PDX models and one cancer cell line with high PDL1 levels were used to test respond to anti-PD1 therapy in hu-NSG-SGM3 mice. Results: Reconstitution of human immune system in the blood was faster and more robust in NSG-SGM3 compared to NSG recipients throughout the course of the study (18 weeks). Human CD45⁺ cells reached 25% of total blood cells at week 4 in hu-NSG-SGM3 mice and at week 9 in hu-NSG mice. A majority of blood hCD45+ cells (55%) in hu-NSG-SGM3 at week 4 were CD33+ myeloid cells. By comparison, efficiency of human CD33+ cells (15%) in the circulation was poor in hu-NSG mice. Moreover, circulating hCD3+ T cells reached 10% at week 9 and included regulatory T cells (Tregs). Hu-NSG mice displayed comparable hCD3+ T cells in the blood only at 12-15 weeks and did not contain Tregs. Tumor-infiltrating myeloid cells will be discussed. High PD-1 expression by CD8⁺T cells and Tregs were present within the breast cancer microenvironment suggesting anergy and immunosuppression in hu-NSG-SGM3 mice. Treatment with the anti-PD-1 receptor antibody pembrolizumab significantly reduced tumor growth and the PD-1 expression level on lymphocytes. Conclusions: PDX-bearing hu-NSG-SGM3 mice might serve as a new and improved platform for preclinical immuno-oncology efficacy studies.