Characterization of the infiltrating immune response to brain metastases after radio- and immunotherapy

• Applicant: Dr. András Piffkó
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: from 2021 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455353745

Brain metastases (BM) are the most common brain tumors in adults and induce significant mortality and morbidity. Despite recent advances in systemic and local treatment options, treatment options are frequently inadequate in containing disease progression and the median survival still rarely exceeds 12 months. During the metastatic process, the immune system can act as a natural selective pressure agent by promoting those tumor cells, which are most well adapted to survive in an immunocompetent setting. The multifaceted effects of the immune system on metastasis evolution also include interactions with the tumor microenvironment (TME) and direct stimulation of tumor growth. However, the effect of these complex selection processes on the development of brain metastases has not yet been comprehensively established and our understanding of carcinogenic mechanisms in BM is limited. Crucial mechanisms that affect cancer-immune interactions within the tumor microenvironment are the programmed death-ligand 1 (PD-L1) / programmed cell death protein 1 (PD-1) axis, which potently impedes anti-tumor T-cell function as well as the cyclic GMP-AMP (cGAMP) – STING (stimulator of IFN genes) pathway, which forms a vital part of the innate immune response to cytosolic double-stranded DNA (dsDNA). Both mechanisms are significantly affected through radiotherapy, which can have dual, in certain cases even opposing effects on cancer-immune interactions. It has been shown that the expression of PD-L1 is increased after irradiation and may therefore suppress local immune responses and facilitate tumor relapse. The combination of IR and immune therapeutic agents, such as anti- PD-L1, can thus act synergistically and improve cancer-specific immune responses by diminishing immunosuppressive mechanisms.Consequently, the aim of this project proposal is to analyze and evaluate the physiological antitumor immune response as well as the pathogenesis of tumor-induced immunosuppression in brain metastasis. We furthermore aim to examine changes to these processes after radiotherapy, immunotherapy and the combination of the two, with specific focus on two mechanisms of which their immediate relevance to cancer-immune interactions has already been proven; STING-induced changes to the myeloid compartment and PD-1 / PD-L1 dependent function of lymphocytes, henceforth aiming to improve our understanding of these complex processes and facilitating the development of translational immunotherapeutic approaches and more personalized cancer therapies.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Ralph Weichselbaum