Impact of epithelial cell plasticity programs on the anti-tumor immune-response

A deeper understanding of the dynamic tumor immune microenvironment (TIME) and the fine-tuned interplay between malignant cells and immune cells are expected to instruct novel rational combination therapy approaches, and suggest an avenue forward for circumventing the emergence of drug-tolerant cells resilient to immune cell mediated killing. Although malignant cells display reduced perception of microenvironment specificity compared to normal or immortal cells, we have shown that specific components of the tumor microenvironment allow the emergence of persister cell phenotypic states through initiation of conserved cellular plasticity programs, as well as non-sporadic induction of clinically actionable receptor tyrosine kinases (RTKs), including KIT and AXL. Cancer cell cooption of epithelial phenotypic plasticity has emerged not only as a mediator of therapy resistance to conventional cancer therapies, but also as a central challenge for the efficacy of immune checkpoint inhibition. This work have elucidated how the microenvironmentally induced epithelial plasticity programs may endow carcinoma cells with a remarkable phenotypic and functional flexibility precluding the successful formation of the carcinoma cell-immune cell synapse which is critical to immune cell mediated carcinoma cell killing. In particular, our results in non-small cell lung cancer (NSCLC) reveal an AXL-mediated immune-escape regulatory pathway, and support AXL as a candidate biomarker for tumors resistant to NK and CTL mediated killing. We have shown that targeting AXL mediated epithelial plasticity may overcome human lung cancer cell resistance to NK- and CTL-mediated cytotoxicity, and we have shown that AXL inhibition induce an immunogenic cell death with the release of DAMPs acting as a TIME adjuvant and thus a positive regulator of the cancer-immunity cycle. We are excited to know that the clinical efficacy of AXL inhibition in combination with immune checkpoint inhibitors is currently being tested in clinical trials.

The final original results of the research has been disseminated as original research articles published in high-impact peer-reviewed international journals (e.g Journal of Thoracic Oncology (2018 impact factor: 12.460, ranking oncology: 10th of 229 journals, respiratory system 3rd of 63 journals), Cancer Immunology Research (impact factor: 8.619). As the results of the proposed project may have important clinical implications, an important aim for the project leader is to communicate the results also in an educational manner to medical doctors and oncologists (patent pending/ ongoing clinical trials), several review articles and book chapters covering the knowledge into the concept of epithelial plasticity and the impact of targeting epithelial plasticity in order to sensitize cancer cells to treatment with immunotherapy has been published in order to provide a wider dissemination of the research to a broader audience of scientists and clinicians.

Avoiding immune destruction has been outlined as one of the emerging hallmarks of cancer. The proposed research project addresses the fundamental question of how epithelial-derived tumor cells evade immune recognition and destruction through coopting epithelial plasticity programs. Our preliminary results show that the receptor tyrosine kinase Axl plays a common role in regulating cell state transitions in normal epithelial stem cells and phenotypic plasticity in aggressive, therapy-resistant carcinoma cells. We predict that tumor cell plasticity will emerge as a crucial and confounding resistance mechanism to cancer immunotherapies, and thus the outlined objectives of this application aims to explore the molecular mechanisms employed by a scientific collaboration with the world-leading experts in cellular plasticity programs (Professor Jean-Paul Thiery) and tumor immunology (Professor Chouaib, Gustave Roussy, Paris). The impact of the Gas6-Axl signaling pathway on immune cell mediated cytotoxisity will be assessed, and the impact of the signaling pathway on the formation and stability of the immunological synapse will be explored. Further an Microenvironment Array (MEArray) platform will be developed and applied as a novel screening tool to identify how microenvironments comprising different combinations ECM proteins, soluble factors and oxygen tension affect tumor cell plasticity and responses to immune cell mediated cell killing. The project plan is designed to support the mobility and scientific career development of a young, early-stage female project leader in the rapidly growing field of cancer immunology. In summary, the project is expected to yield unique insight into the underlying mechanisms of tumor immune evasion by a therapeutically actionable signal transduction system. This knowledge will have important therapeutic implications and can provide a conceptual basis for development of new therapeutic strategies in cancer treatment.