Mice with humanized immune systems test new cancer therapeutic approach that blindfolds immune cells to the body’s self-recognition system

NewsGuard 100/100 Score

In a recent study published in Frontiers in Immunology, researchers investigated the anticancer effects of drugs targeting human tumor-associated macrophages (TAMs) in vivo. In humanized murine models, they tested the effectiveness of an antibody to human signal regulatory protein alpha (SIRPα) for cancer immunotherapy.

Study: Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models. Image Credit: Lightspring/Shutterstock.com
Study: Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models. Image Credit: Lightspring/Shutterstock.com

Background

TAMs are prospective targets for cancer immunotherapy due to their anti-inflammatory and anticancer characteristics. TAM reprogramming from pro-tumoral to antitumoral states may lead to novel cancer treatments. SIRPα is a protein from the immunoglobulin superfamily that interacts with a cluster of differentiation 47 (CD47) to form an innate immunological checkpoint.  

In immunocompromised mice, an antibody that could block the interaction between SIRPα and CD47 could increase the inhibitory effects of rituximab (human CD20 antibody) on B-cell lymphoma development. Humanized immune system (HIS) mice are critical for assessing the anticancer effects of treatments that target human immune cells.

About the study

In the present study, researchers extended their previous analysis by performing a preclinical analysis using a model simulating human tumor-related macrophages in the tumor microenvironment (TME) to evaluate the therapeutic efficacy of antibodies against hSIRPα (anti-hSIRPα).

The team intended to gain insight into the anticancer activity of a human SIRPα antibody (SE12C3), which inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and increases Fc receptor-mediated phagocytosis of the former by the latter. They developed preclinical tumor xenograft models using immunodeficient mice expressing numerous human cytokines reconstructed with HIS by transplanting a cluster of differentiation 34-positive hematopoietic stem and progenitor cells (HIS-MITRG) murine animals. The team developed MISTRG mice, which help the growth of human myeloid cells by replacing murine cytokine-related genes with human orthologs.

HIS-MISTRG murine animals also exhibit functional-type differentiation of human tumor-related macrophages within the tumor microenvironment. The researchers created human cell- or patient-obtained B-cell lymphoma xenograft models in HIS-MITRG murine animals to examine human TAM-mediated anticancer responses. They obtained fresh umbilical cord blood cells (UBC) diffuse large B-cell lymphoma (DLBCL) specimens and produced mouse monoclonal antibodies against hSIRPα. They used HIS-MITRG mice to prevent binding to hSIRPα expressed on mouse macrophages to investigate whether anti-hSIRPα may improve the antitumor activity of rituximab in vivo.

The researchers examined human immunological cells in tumor-bearing HIS-MITRG murine animals and tumor-infiltrating immune cells after antibody treatment. They also explored the involvement of macrophages in the anticancer impact of SE12C3 and rituximab therapy in HIS-MITRG murine animals. They studied TAMs in the TME BY ribonucleic acid sequencing (RNA-seq). They created a renal subcapsular patient-derived xenograft (PDX) model of DLBCL by implanting primary tumor tissue in the renal subcapsular area of an MITRG mouse. They next investigated the influence of engrafted human immune cells on PDX tumor growth and that of rituximab and SE12C3 therapy on DLBCL tumor growth.

Results

The team used HIS-MITRG murine animals to assess the development of human Raji cell line- and patient-obtained B-cell lymphoma and human macrophage infiltration into their neoplasms. The SE12C3 and rituximab combination treatment suppressed Raji tumor development in HIS-MITRG murine animals more robustly than rituximab monotherapy. Improved anticancer activity depended on human macrophage cells due to increased rituximab-dependent lymphoma cell phagocytosis by human macrophages. The combined antibody treatment also caused human TAM reprogramming toward a pro-inflammatory phenotype.

Furthermore, in HIS-MITRG murine animals, the combined therapy effectively inhibited patient-derived diffuse large B-cell lymphoma formation. The results revealed a TAM-dependent anticancer impact of anti-hSIRPα combined with rituximab, which seemed to initiate TAM reprogramming from protumoral to antitumoral states. In HIS-MITRG murine animals, human immunological cells aided tumor progression. In HIS-MITRG murine animals, the hSIRPα Ab SE12C3 improved rituximab-induced suppression of B-cell lymphoma development. Rituximab treatment with or without SE12C3 increased human macrophage infiltration in HIS-MITRG malignancies.

The tumor growth rate and weight in HIS-MITRG murine animals were considerably higher than in identically injected MITRG animals. Tumor tissue was invaded by hCD68+ macrophages, particularly hCD163+ macrophages, giving it a starry-sky appearance. The interaction of hCD47 on Raji cells and hSIRP on human macrophages impedes tumor cell phagocytosis. Rituximab therapy significantly decreased RajiGFP/Luc tumor development in HIS-MITRG murine animals, and combined antibody treatment elevated HLA-DR+hCD14+ macrophage counts in each gram of cancer tissue. SE12C3 increased human macrophage phagocytosis of Raji cells in response to rituximab

Conclusion

Overall, the study findings found that using HIS-MITRG murine animals as a model for preclinical assessment of prospective therapies targeting human TAMs increased B-cell lymphoma development and tumor invasion. However, the mechanisms underlying the simulation of lymphoma formation by human myeloid cells in HIS-MITRG murine animals are unknown. TAMs in the CDX model, on the other hand, exhibited the M2-like macrophage marker CD163.

Blocking the CD47-SIRP interaction is a potential TAM-directed therapeutic strategy for encouraging macrophage antibody-dependent cellular phagocytosis (ADCP) in tumor cells. Further research is required to validate these animals as human syngeneic tumor models for in vivo testing of therapies targeting human macrophages.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

Citations

Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Toshniwal Paharia, Pooja Toshniwal Paharia. (2023, December 19). Mice with humanized immune systems test new cancer therapeutic approach that blindfolds immune cells to the body’s self-recognition system. News-Medical. Retrieved on April 20, 2024 from https://www.news-medical.net/news/20231219/Mice-with-humanized-immune-systems-test-new-cancer-therapeutic-approach-that-blindfolds-immune-cells-to-the-bodye28099s-self-recognition-system.aspx.

  • MLA

    Toshniwal Paharia, Pooja Toshniwal Paharia. "Mice with humanized immune systems test new cancer therapeutic approach that blindfolds immune cells to the body’s self-recognition system". News-Medical. 20 April 2024. <https://www.news-medical.net/news/20231219/Mice-with-humanized-immune-systems-test-new-cancer-therapeutic-approach-that-blindfolds-immune-cells-to-the-bodye28099s-self-recognition-system.aspx>.

  • Chicago

    Toshniwal Paharia, Pooja Toshniwal Paharia. "Mice with humanized immune systems test new cancer therapeutic approach that blindfolds immune cells to the body’s self-recognition system". News-Medical. https://www.news-medical.net/news/20231219/Mice-with-humanized-immune-systems-test-new-cancer-therapeutic-approach-that-blindfolds-immune-cells-to-the-bodye28099s-self-recognition-system.aspx. (accessed April 20, 2024).

  • Harvard

    Toshniwal Paharia, Pooja Toshniwal Paharia. 2023. Mice with humanized immune systems test new cancer therapeutic approach that blindfolds immune cells to the body’s self-recognition system. News-Medical, viewed 20 April 2024, https://www.news-medical.net/news/20231219/Mice-with-humanized-immune-systems-test-new-cancer-therapeutic-approach-that-blindfolds-immune-cells-to-the-bodye28099s-self-recognition-system.aspx.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment
Post

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
New Lancet Commission on Breast Cancer: Transforming breast cancer care globally