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Research Projects

Sibilia Lab

Immunomodulation in Inflammation and Cancer

Our laboratory is interested in understanding the molecular mechanisms leading to inflammatory diseases and cancer using the mouse as a model system. We investigate the cell-specific role of EGFR signaling in cancer and tumor stromal cells and their complex interaction.

Moreover, we aim to understand how inflammatory cells affect tumor development and regression and exploit novel concepts to modulate tumors to become more sensitive to current cancer treatments.

The ultimate goal is to translate this knowledge to patients to develop more effective personalized treatments for human cancer.

EGFR signaling in cancer development and inflammation

EGFR overexpression or mutations are present in many human tumors of epithelial and glial origin and targeted anti-EGFR therapies are currently used for cancer treatment. Until now the tumor-promoting function of the EGFR was exclusively linked with its expression in tumor cells.

Our laboratory has recetly discovered that in liver tumors (HCC) EGFR is upregulated in liver macrophages (also called Kupffer cells) (Figure 1), where it plays a tumor-promoting function by regulating the expression of cytokines such as IL-6.

By employing genetically engineered mouse models (GEMMs), we demonstrated that deletion of EGFR in macrophages dramatically reduces liver cancer development, whereas EGFR deletion in tumor cells is even accelerating tumor growth.

Also in HCC patients we could demonstrate that the presence of EGFR positive macrophages is a bad prognostic factor for disease-free and overall survival of patients. This tumor-promoting function of EGFR in non-tumor cells is very important for precision oncology as it allows a better stratification and more effective treatment of liver cancer patients for which there are still no therapeutic options (Lanaya et. al. Nature Cell Biology, 2014).

A similar observation was made in in human CRC where we detected EGFR positive myeloid cells in the tumor microenvironment, which correlated with poor survival in metastatic patients. In CRC mouse models we demonstrated that EGFR inhibition in myeloid cells reduces tumor growth whereas therapeutic deletion of EGFR in tumor cells does not. These finding force us to re-evaluate the mechanism by which anti-EGFR drugs are effective in tumors.

The majority of cancer patients receiving anti-EGFR therapies also develop a severe skin inflammation, which positively correlates with the anti-cancer treatment response. Mice lacking EGFR in the epidermis develop severe hair follicle defects and skin inflammation similar to what observed in patients receiving anti-EGFR therapies.

Using GEMMs and patient skin samples we could show that EGFR inhibition leads to the upregulation of inflammatory cytokines and breakdown of the skin barrier (Figure 2). An in depth understanding of the molecular mechanisms at the basis of these defects will greatly contribute to develop strategies aimed at alleviating the side effects of patients receiving anti-EGFR drugs.

Function of innate immune cells in tumor development

GEMMs are also employed to analyze the role of innate immune cells like plasmacytoid DCs (pDCs) in inflammation and cancer with the aim to find therapeutic intervention strategies to enhance innate immunity against tumors. We discovered that if pDC are activated by Imiquimod, a Toll-like receptor (TLR) 7/8 agonist used in the clinic to treat basal cell carcinomas, they can be converted into “killer cells” capable of clearing tumors without the need of the adaptive immune system (Drobits et. al. JCI, 2012). Thus, Imiquimod or equivalent drugs could serve as a useful adjuvant and immunotherapeutic agents capable of skewing inflammatory responses towards tumor inhibiting and tumor killing responses (Figure 3).

Therapeutic targeting of EGFR in colorectal cancer as a novel approach to predict and enhance tumor antigenicity and response to checkpoint inhibitors

Despite the big success of checkpoint inhibitors for cancer treatment, many patients like microsatellite stable metastatic colorectal cancer (mCRC) patients fail to respond for reasons that are poorly understood.

One standard therapy for mCRC with wildtype RAS is EGFR inhibition combined with chemotherapy. However, for unknown reasons, many patients do not profit from this therapy.

Using genetically engineered mouse models (GEMM) we identified a tumor-promoting role of EGFR-expressing myeloid cells in CRC and could demonstrate that EGFR positive myeloid cells are a bad prognostic factor for mCRC patients. We thus hypothesize that EGFR-expressing myeloid cells adopt a pro-tumorigenic phenotype by creating an immunosuppressive environment. EGFR blockade could therefore revert this by increasing immunity against tumors and enhancing the effectiveness of checkpoint inhibitors.

We have therefore assembled a group of experts in oncology, bioinformatics and molecular biology to test this hypothesis by employing GEMM of CRC lacking EGFR in different cells combined with mouse and human next generation sequencing of tumor, stromal, and immune cell populations. The complex interplay between mutations in tumor cells and stroma will be tackled by investigations on large patient cohorts combined with mechanistic studies in GEMM. We expect to identify factors conferring resistance to immunotherapy in microsatellite stable CRC patients with the aim to improve precision oncology in mCRC.