Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer in the clinic. Further discovery of novel drugs or therapeutic protocols that enhance efficacy requires reliable animal models that recapitulate human immune responses to ICI treatment in vivo. In this study, we utilized an immunodeficient NOG mouse substrain deficient for mouse FcγR genes, NOG-FcγR−/− mice, to evaluate the anti-cancer effects of nivolumab, an anti-programmed cell death-1 (PD-1) antibody. After reconstitution of human immune systems by human hematopoietic stem cell transplantation (huNOG-FcγR−/− mice), four different programmed death-ligand 1 (PD-L1)-positive human cancer cell lines were tested. Among them, the growth of three cell lines was strongly suppressed by nivolumab in huNOG-FcγR−/− mice, but not in conventional huNOG mice. Accordingly, immunohistochemistry demonstrated the enhanced infiltration of human T cells into tumor parenchyma in only nivolumab-treated huNOG-FcγR−/− mice. Consistently, the number of human T cells was increased in the spleen in huNOG-FcγR−/− mice by nivolumab but not in huNOG mice. Furthermore, human PD-L1 expression was strongly induced in the spleen of huNOG-FcγR−/− mice. Collectively, our results suggest that the anti-cancer effects of anti-PD-1 antibodies can be detected more clearly in NOG-FcγR−/− mice than in NOG mice.
Highlights
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer in the clinic
Mouse strains highly tolerant to xenogeneic tissues such as NOD/Shi-scid-IL2Rγnull (NOG)[22], NOD/LtSz-scidIL-2Rγnull (NSG)[23], and BALB-RAG2−/− IL-2Rγ−/− double knockout (BRG) mice expressing human signal-regulatory protein α (SIRPA) (BRGS)[24,25] are frequently used for transplanting human hematopoietic stem cells or human peripheral blood mononuclear cells
Analysis of PB from the reconstituted mice demonstrated that the frequency of human CD45+ leukocytes in the total leukocytes was higher in huNOG-FcγR−/− mice than in huNOG mice from 8 to 16 weeks post HSC transplantation (Fig. 1a)
Summary
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer in the clinic. Mouse strains highly tolerant to xenogeneic tissues such as NOD/Shi-scid-IL2Rγnull (NOG)[22], NOD/LtSz-scidIL-2Rγnull (NSG)[23], and BALB-RAG2−/− IL-2Rγ−/− double knockout (BRG) mice expressing human signal-regulatory protein α (SIRPA) (BRGS)[24,25] are frequently used for transplanting human hematopoietic stem cells (huHSCs) or human peripheral blood mononuclear cells (huPBMCs). In these mouse strains, the lack of rearrangement in the B-cell receptor and T-cell receptor genes due to the scid mutation or RAG deficiency prevents the development of mature mouse B and T cells. Improvement of animal models by identifying key obstacles is critical for the accurate evaluation of ICIs in humanized mice
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