Report
Teaser, summary, work performed and final results
Periodic Reporting for period 2 - TNT-TUMORS (Therapeutic approaches to enhance innate immunity against Tumors)
Teaser
In the past decade the use of targeted therapies has led to an average gain in progression-free survival of only few months for cancer patients with advanced, refractory or metastatic disease indicating that there is an urgent need for novel therapeutic concept to cure cancer...
Summary
In the past decade the use of targeted therapies has led to an average gain in progression-free survival of only few months for cancer patients with advanced, refractory or metastatic disease indicating that there is an urgent need for novel therapeutic concept to cure cancer. A recent big breakthrough in cancer therapy has been the use of checkpoint inhibitors with significantly higher survival benefits for patients with metastatic disease. However, a large fraction of patients fail to respond to checkpoint blockades for reasons that are poorly understood. Moreover, effective biomarkers predicting response to immunotherapy are basically missing. It has long been recognized that cancer progression and therapy response strongly depend on the immune cell composition of the tumor microenvironment. Several strategies are currently being investigated to enhance immunogenicity of tumors and boosting T-cell mediated anti-tumor immunity. An alternative approach is to modulate innate immune cells.
Therefore the major goal of TNT-TUMORS is to increase our understanding of the cellular and molecular mechanisms controlling the tumor-promoting characteristics of innate immune cells by focusing on plasmacytoid Dendritic cells (pDC) and myeloid cells/macrophages. Both these cell types infiltrate solid tumors and if properly modulated they may adopt anti-tumorigenic properties and enhance the effectiveness of current modern anti-cancer treatments. This project therefore aims at identifying new targets and strategies that prevent these cells from acquiring pro-tumorigenic functions and endow them with anti-tumorigenic properties with the final objective to identify novel therapeutic approaches to enhance innate immunity against tumors. Inducible and cell-specific genetic mouse models mimicking human cancers will allow to molecularly dissect the immunmodulatory capacity of pDCs and TAMs. State-of-the-art large scale in vitro and in vivo RNAi screens will provide a platform to identify novel molecular pathways and open the possibility for testing new strategies in cancer immunotherapy. The clinical significance of our findings will be validated in human cancer samples and a close cooperation with clinicians ensures a fast predictive and therapeutic translation of our results. A deeper understanding of these mechanisms will be of fundamental importance to develop more effective and possibly curative therapies aimed at treating tumors and, most essentially, metastatic disease.
Work performed
During the first 30 months, we performed important experiments on all proposed aims which resulted already in publications.
In TNT-TUMORS we had proposed to study two types of innate immune cells, namely pDCs and myeloid cells/macrophages and find way how to modulate them to attack tumor cells and to enhance the effect of standard anti-cancer therapies. Using the mouse as a model system we had identified two independent mechanisms by which modulation of pDCs and EGFRpositive myeloid cells (EGFR+ TAM) inhibited the growth of solid tumors. We had shown that stimulation of pDCs with TLR agonists could transform them into cells capable of directly killing tumor cells without the need of the adaptive immune system. Second, we identified a tumor-promoting role of EGFR+ TAMs during colorectal cancer (CRC) and hepatocellular carcinoma (HCC) formation. This enabled us to look at the role of EGFR in tumorigenesis in a completely different way as most of the previous studies had associated the oncogenic function of the EGFR to its expression in tumor cells. Thus, the mechanism by which anti-EGFR drugs are effective in tumors needs to be re-evaluated.
Aim 1: We have characterized AP1 as an important transcription factor controlling pDCs activation and recruitment during TLR-induced anti-tumor responses. We could also define the mechanisms behind the systemic and topical effects mediated by IMQ in anti-tumor immunity.
Aim 2: We have established the necessary cellular assays and co-culture systems to identify factors that lead to EGFR upregulation in macrophages and have characterized EGFR positive macrophages for their basic physiological functions.
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Aim 3: We showed that inducible EGFR deletion in tumor cells of CRC does not impinge on tumor growth (Srivatsa, Paul et al. Gastroenterology, 2017). We have switched to tumor organoid models to more efficiently address the proposed scientific questions.
Aim 4: We characterized human CRC samples and were able to detect EGFR positive myeloid cells in these tumors and correlate their presence to a worse overall survival of metastatic CRC patients (Srivatsa, Paul et al. Gastroenterology, 2017). We could also establish a direct link between the presence of EGFR positive myeloid cells and the response of CRC patients to anti-EGFR treatment.
Final results
We expect to identify novel targets that can be modified for efficient transformation of pDCs into tumor killing cells. Moreover, we will identify the tumor-surveillance mechanisms mediated by EGFRpositive myeloid cells. With these findings, we anticipate to improve immune-based anti-cancer treatment in future.