Immuno-thermal therapy for targeting immune networks to control melanoma metastasis

01.01.2022 bis 31.12.2022

Immunotherapy is an emerging first-line treatment to target advanced cancer, with the potential to reach long-lasting regression and cure. Most solid tumors initially respond to immunotherapy; however, the majority of patients experience therapy-resistance followed by relapse. Cell-based immunotherapies focus on activating or directly engineering tumor-specific cytotoxic cells (CTL), which are infused in the patient to mediate tumor elimination. However, a successful immune response is controlled by a network of highly-specialized immune cell subtypes which, in response to functional parameters of the microenvironment, steer immune decisions towards tolerance or anti-tumor effector function. Consequently, CTL can be found infiltrating the tumor in patients, but their killing capacity is often rapidly shut-down by local, suppressive immune networks. Fever-range thermal therapy is a potential strategy to convert immunosuppressive tumor tissue niches into a proinflammatory microenvironment. Thermal therapy is a clinically emerging therapy that is based on strong biological rationale and is empirically effective, but largely lacks a mechanistic framework. By using a world-wide unique multiscale imaging workflow, consisting of (i) in vivo intravital multiphoton microscopy (iMPM) of the primary melanoma lesion, (ii) ex vivo 3D light-sheet microscopy (LSM) of melanoma metastases and (iii) translational immuno-PET/MR imaging of systemic immune activation and function, we aim to decipher the molecular and cellular mechanisms that mediate immuno-thermal therapy efficacy and potential side effects. A deeper understanding of the interplay between immuno- and thermal therapies will allow to better exploit synergistic mechanisms to achieve sustained melanoma remission.