Christoph Iselin, MD-Phd in the laboratory of Prof. Emmanuella Guenova (UNIL) – (Cutaneous Lymphoma)

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Christoph Iselin was awarded this “MD-PhD scholarship” in May 2023 for 3 years. He is performing his research in Prof. Emmanuella Guenova’s lab at the University of Lausanne.

Cutaneous T cell lymphoma (CTCL) is a group of rare but potentially lethal non-Hodgkin’s lymphomas, originating from malignant CD4+ T cells. The patient’s immune system is deemed an important determining factor of disease progression, and immunomodulatory therapies reliably improve outcomes. Therefore, understanding the effect of CTCL on the immune system and its cells is imperative for improving therapeutic options.

CTCL immunomodulatory effects lead to immune cell exhaustion, explaining the so far disappointing results of T- and dendritic cell-dependent therapies when compared to other types of cancer. However, there is recent evidence that natural killer (NK) cells account for the response of immunomodulatory treatment in CTCL.

Given the immunomodulatory nature of CTCL, its profoundly immunosuppressive tumor microenvironment and the reduced anti-tumor activity of NK cells in CTCL patients, I formulate the following hypothesis: the tumor microenvironment-driven suppression of NK cell function is a crucial factor for tumor progression in CTCL, and the rescue of NK cell activity can be used as an effective treatment strategy in CTCL and cancer in general.

The overarching goal of this project is to reverse the CTCL-impaired NK cell activity by targeting the factors which negatively regulate NK cell function. The first step will be to phenotype the NK cells in the tissue microenvironment (TME) of CTCL through computational, single-cell sequencing analysis. I will examine this comprehensive dataset for factors and pathways that specifically alter NK cells in CTCL by comparing it with that of the NK cells in healthy skin, inflammatory skin diseases and solid skin tumors.

All discovered candidate molecules will then be individually validated by reverse transcription PCR (RT-PCR), fluorescence-activated cell sorting (FACS) and protein immunoblotting in NK cells from CTCL patients and individuals suffering from the aforementioned other diseases as controls. The number and state of activity of NK cells will be compared to the existing patient-specific clinical data to evaluate the impact of disease stage and progression. I will then test the reversibility of the suppressive effect of promising candidate molecules on NK cell activity in vitro and develop a combinatorial therapy plan to treat CTCL in a syngeneic T cell lymphoma model. In this way, I will test in vivo whether the target molecules discovered in steps 1 and 2 can be used to rescue the anti-tumor potential of NK cells and improve the outcome of CTCL.

If successful, this project will advance our understanding of the role of NK cells in CTCL pathology and treatment, as well as in inflammatory skin diseases and solid skin tumors. The factors and pathways initially identified through computational analysis, experimentally validated in vitro as reversible and found to be effective in vivo can be the basis for further studies to test their clinical applicability.