Periodic Reporting for period 1 - iGEMMdev (Development and Characterisation of New Immunogenic GEMMs of Lung Cancer)
Période du rapport: 2017-01-01 au 2018-12-31
To understand how these drugs work and which ones will be the best to use for which patients, we have to use pre-clinical models. Because these drugs are working by changing the effect of the immune system on the tumour, we have to work with a whole animal where these systems are present. Unfortunately, the models which we have been using in the lab for years are not useful for studying this kind of therapy. Lung cancer in human has many mutations, and this is these mutations that the immune system can detect to recognise the tumour and to eliminate it. The mouse models of lung cancer we have been using so far have no mutations and therefore, could not be seen by the immune system making them useless to study immunotherapy. This project aimed to induce mutations in mouse lung tumours to make them more similar to their human counterpart and to make the immune system of these mice able to see the tumours.
We developed and characterised three models of lung adenocarcinoma. From the two models that we had initially planned to generate, the KP-A3Bi model has not proven to be more immunogenic than the reference model of lung cancer in standard conditions. However, the immunogenic cell line we established from this model demonstrated that some clones within the KP-AB3i tumours can be recognised and controlled by the immune system. We are still working at finetuning this model to improve it. The second model, KP-M2, has just been developed and is still being characterised. We adapted our initial plan and added chemicals (carcinogens) to our transgenic models to increase the number of mutations in tumours. The U-A3Bi model resulting from this showed a partial response to immunotherapy. Altogether, this suggests that A3Bi (APOBEC3B) is an excellent candidate to induce mutations that are recognised by the immune system and therefore useful in the development of an immunogenic genetically engineered mouse model (or iGEMM) of lung cancer.
The characterisation of the two iGEMMs we planned to develop during this project will need more work before we can submit an article. In contrast, the transplant model and the conditional model we developed are both already used in 3 other projects which are expected to be published in high impact factor journals.
Our conditional model of lung cancer provides a tool to study immunological aspects of cancer but also resistance to treatment. It will be useful at different levels. It provides access to an immunologic cancer model other than subcutaneous transplant models which do not recapitulate the tumour microenvironment observed in the tissue where tumours develop. It can become standard in preclinical studies in lung cancer because: 1) Genomic alterations and consequent Intratumoural Heterogeneity (ITH) lead to more complex tumours and increase the difficulty to cure them because of subclones resistant to treatment. The model we developed mirrors this ITH allowing the study of its impact on drug resistance. 2) Therapies that aim to stimulate the immune system could lead to severe autoimmune toxicity. The opportunity to assess these possible toxicities on a relevant mouse model is crucial to limit patients risk exposure.
The models developed here will give new insights into the immunological aspects of lung cancer and consequently, will maximise the potentials of immunotherapies to cure cancer.