Autologous humanized mouse models of iPSC-derived tumors enable characterization and modulation of cancer-immune cell interactions

Moquin‐Beaudry, Gaël; Benabdallah, Basma; Maggiorani, Damien; Lê, Oanh; Li, Yuanyi; Colas, Chloé; Raggi, Claudia; Ellezam, Benjamin; M'Callum, Marie-Agnès; Soglio, Dorothée Dal; Guimond, Jean; Paganelli, Massimiliano; Haddad, Élie; Beauséjour, Christian

doi:10.1016/j.crmeth.2021.100153

Cited by 14 publications

(19 citation statements)

References 52 publications

(58 reference statements)

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“…MC38 and EL-4 cells were grown in DMEM or RPMI1640 respectively (Multicell) supplemented with 10% FBS and 1% penicillin-streptomycin at 37 °C under 5% CO2 in a humidified atmosphere. MC38 tumor cells were transduced with a lentivector to express mPlum 63 and sorted to obtain a nearly pure population with high mPlum fluorescence. Cells are routinely tested to ensure the absence of mycoplasma contamination.…”

Section: Methodsmentioning

confidence: 99%

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Maggiorani,

Le,

Lisi

et al. 2024

Nat Commun

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The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

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Section: Methodsmentioning

confidence: 99%

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Maggiorani,

Le,

Lisi

et al. 2024

Nat Commun

Self Cite

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“…In addition, the generation of HLA-restricted tumour antigen-specific T cells is challenging owing to the HLA mismatch and lack of a human thymic epithelium that supports T cell development. Autograft tumour models (Table 3) have several advantages that would potentially enable the generation of HLA-restricted, tumour antigen-specific T cell responses and would reproduce the phenotype and therapeutic response in patients more faithfully than allograft models 61,62,120,[236][237][238][239] . An autograft Hu-SRC model would require the presence of HLA class I and II molecules for optimal T cell development and function.…”

Section: Future Directionsmentioning

confidence: 99%

Humanized mouse models for immuno-oncology research

et al. 2023

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Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.• Next-generation humanized mouse models are being generated to better recapitulate the development of human innate and adaptive immunity. The development and use of novel humanized mouse platforms will accelerate the discovery and testing of new immunotherapies for patients with cancer.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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“…The limitations of this model are mainly the requirement of pre-experimental sub-lethal γ-irradiation to enable engraftment and the limited maturation of human T cells in the murine thymus ( 121 ). To promote the development of T cells in a human thymus-like environment, researchers have co-implanted human CD34+ HSPCs and autologous fetal thymus tissue into SCID mice, generating a mouse model named BLT (bone marrow - liver - thymus) ( 129 ).…”

Section: In Vivo Models To Mimic Bc Complexitymentioning

confidence: 99%

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity

et al. 2023

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Breast cancer is a highly heterogeneous disease, at both inter- and intra-tumor levels, and this heterogeneity is a crucial determinant of malignant progression and response to treatments. In addition to genetic diversity and plasticity of cancer cells, the tumor microenvironment contributes to tumor heterogeneity shaping the physical and biological surroundings of the tumor. The activity of certain types of immune, endothelial or mesenchymal cells in the microenvironment can change the effectiveness of cancer therapies via a plethora of different mechanisms. Therefore, deciphering the interactions between the distinct cell types, their spatial organization and their specific contribution to tumor growth and drug sensitivity is still a major challenge. Dissecting intra-tumor heterogeneity is currently an urgent need to better define breast cancer biology and to develop therapeutic strategies targeting the microenvironment as helpful tools for combined and personalized treatment. In this review, we analyze the mechanisms by which the tumor microenvironment affects the characteristics of tumor heterogeneity that ultimately result in drug resistance, and we outline state of the art preclinical models and emerging technologies that will be instrumental in unraveling the impact of the tumor microenvironment on resistance to therapies.

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Autologous humanized mouse models of iPSC-derived tumors enable characterization and modulation of cancer-immune cell interactions

Cited by 14 publications

References 52 publications

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Humanized mouse models for immuno-oncology research

The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity

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