![]() NOD/LtSz-scid/scid mice lack functional lymphoid cells and show little or no serum Ig with age. Philadelphia (PA): AACR Cancer Res 2019 79(13 Suppl):Abstract nr 1522.The scid mutation was backcrossed ten generations onto the NOD/Lt strain background, resulting in an immunodeficient stock (NOD/LtSz-scid/scid) with multiple defects in adaptive as well as nonadaptive immunologic function. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019 2019 Mar 29-Apr 3 Atlanta, GA. NovelNOD- scid IL2rg null(NSG)mice for preclinical evaluation of TLR agonists in cancer immunotherapy. Whalen, Leonard Shultz, James Keck, Michael Brehm. These findings demonstrate that NSG -TLR4 nullmice are an effective tool to test TLR4 agonists for the ability to activate human immunity and to assess impacts on tumor growth in the absence of the confounding effects of the murine innate immune system.Ĭitation Format: Ken-Edwin Aryee, Lisa Burzenski, Dale Greiner, Giles F. Lastly, LPS challenge of HSC-engrafted NSG-TLR4 nullmice bearing a PDX melanoma significantly reduced tumor growth kinetics. Moreover, both HSC-engrafted NSG- TLR4 nulland NSG mice show similar activation profiles of human innate immune cells and human cytokine production following challenge with LPS. Our results show that human immune system development in HSC-engrafted NSG- TLR4 nullmice is comparable to HSC-engrafted NSG mice with similar levels of human CD45+ cells, CD3+ T cells, CD20+ B cells, and CD33+ myeloid cells detectable in blood and spleen. To validate the NSG- TLR4 nullmouse, we humanized these mice with HSC and evaluated human immune system development and function as compared to HSC-engrafted NSG mice. Challenge of unengrafted NSG- TLR4 nulland NSG- IFNR1 nullmice bearing a PDX melanoma with LPS and poly(I:C), respectively, had minimal impact on tumor growth kinetics, confirming the utility of these novel NSG strains to study specifically human immune responses to TLR agonists. To address this issue, we have created NSG mice lacking TLR4 and Type 1 IFNR1 that fail to respond to LPS and poly(I:C), respectively. Thus differentiating between human and mouse responses to TLR agonist is difficult in currently available NSG mice. Moreover, LPS or poly(I:C) challenge of NSG bearing a PDX melanoma significantly delays tumor growth kinetics in the absence of an engrafted human immune system. Challenge of unengrafted NSG mice with either LPS or poly(I:C) stimulates production of mouse cytokines and maturation of murine innate immune cells. While NSG mice lack murine adaptive immunity (T and B cells), these mice maintain a residual innate immune system with the potential to respond to TLR agonists. Our laboratory uses NSG mice that have been humanized with hematopoietic stem cells (HSC) to study human immunity and to evaluate therapeutics. Currently there is a paucity of preclinical models to evaluate the efficacy of TLR agonists in activating human immune responses and to assess the impact on tumor growth.Humanized mice are emerging as an exciting translationalplatform to study human immuno-oncology and provide tools to test new immunotherapies. Although only two forms of TLR agonists are currently FDA approved for cancer treatment, Bacillus Calmette-Guerin and monophosphoryl lipid A, several clinical trials are ongoing with new TLR agonists, including trials targeting TLR3 and TLR4 pathways. The inflammation induced by TLR agonists is thought to stimulate tumor-specific immunity in patients and augment control of tumor burden. TLR agonists that induce inflammation have been used since the 18 thcentury for the treatment of cancer. ![]()
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