MESHCAP (exogenous microbiota and humanized mice for lung cancer): Towards an innovative preclinical model for testing immunotherapies

Small cell lung cancer (SCLC) is the most aggressive subtype of lung cancer. The recent combination of chemotherapy with immune checkpoint inhibitors shows a response in only 10 to 15% of patients. At the same time, numerous studies highlight the impact of gut microbiota composition on the response to immunotherapy. To address these current challenges, we are developing a xenograft model called "MESHCAP." This model involves grafting circulating tumor cells (CTCs) from SCLC patients onto mice that have been humanized for both their immune system and their gut microbiota. With its unique dual humanization, this model will allow us to take into account the influence of the microbiota when testing new therapeutic strategies. Based on the literature, we have identified a bacterial consortium hypothesized to be beneficial for the response to immunotherapy. This consortium is cultured in the laboratory and then inoculated into immunodeficient mice whose endogenous microbiota has been previously depleted by antibiotic treatment. We are able to detect the presence of these bacteria in the feces by 16S sequencing more than a month after inoculation. In parallel, we have humanized the immune system of immunodeficient mice by injecting human CD34+ hematopoietic stem cells. This engraftment results in chimerism of the mouse immune system. Currently, we are developing the generation of doubly humanized mice for both the microbiota and the immune system. Preliminary data suggest a cross-talk between the humanized microbiota and the human immune system. In our laboratory, we routinely isolate CTCs from patients diagnosed with CTC. We then inject them subcutaneously to generate CDXs (CTC-derived xenografts). It is these CDXs that we will implant into our doubly humanized mouse model to investigate the impact of the microbiota and immune system on therapies (e.g. immunotherapy).