Deciphering the tumor-immune-microenvironment profile and organization within the tumors of melanoma patients undergoing immunotherapy

Projektbeschreibung

Zusammenspiel von Tumorzellen, Tumormikroumgebung und Immunsystem

Das Fortschreiten einer Krebserkrankung ist ein komplexer Prozess, der vom Zusammenspiel zwischen Tumorzellen, der Tumormikroumgebung und dem Immunsystem beeinflusst wird. Um die Tumorbiologie und das Ansprechen auf die Behandlung besser zu verstehen, ist es notwendig, die Proteinexpression des gesamten miteinander verbundenen Systems zu profilieren. Flugzeit-Ionenstrahlbildgebung (Multiplexed Ion Beam Imaging by Time of Flight, MIBI-TOF) ist ein technisches Verfahren, bei dem an Metalle konjugierte Antikörper eingesetzt werden, um gleichzeitig dutzende Proteine in Proben intakter Gewebe mittels Sekundärionen-Massenspektrometrie sichtbar werden zu lassen. Das EU-finanzierte Projekt MelImmuneOrg verfolgt das Ziel, das Immunprofil von Tumoren und die Organisation innerhalb von diesen bei Melanompatienten zu enträtseln, die sich einer Immuntherapie unter Einsatz von MIBI-TOF unterziehen. Die intratumorale Heterogenität und die genetischen Korrelationen zwischen Tumor, Immunmikroumgebung und Ansprechen auf die Therapie sollen analysiert werden.

Ziel

Cancer progression is a complex process that depends on the interplay between tumor cells, tumor microenvironment, and the immune system. Inhibiting immunosuppression is beneficial for cancer patients. Although these therapies are promising they are successful only in part of the patients. Tumors are composed of distinct cell types with different phenotypes, that influence the efficacy of immunotherapies. Therefore, in order to better understand tumor biology and response to treatment, it is necessary to profile protein expression while preserving spatial information. Multiplexed Ion Beam Imaging by Time of Flight (MIBI-TOF) is a method in which antibodies conjugated to metals are used to simultaneously visualize dozens of proteins in intact tissue specimens by secondary ion mass spectrometry. Here we suggest to uncover the immune profile and organization within the tumors of melanoma patients undergoing immunotherapy using MIBI-TOF. My first objective is to characterize the tumor-immune microenvironments to understand how these are structured across patients and discover predictive features of response to immunotherapies. My second objective is to analyze the intratumor heterogeneity (ITH) of melanoma patients by exome sequencing. I will examine whether there are genetic correlates between ITH, immune microenvironment and response to therapy. Finally, my third objective will be the manipulation of individual hits to test their functional significance in tumor-immune architecture in murine models. By joining Dr. Keren’s lab that masters the MIBI-TOF technology, I will acquire this state-of-the art technique, as well as develop lab management and organization skills, and I will meet leader scientists from the immune-oncology field. This proposal will promote my competitiveness to gain an independent researcher position.