Blockade of Adenosine-driven Immune Suppression in Brain Metastasis to Overcome Resistance against Immunotherapy

• Applicant: Professorin Dr. Lisa Sevenich, Ph.D.
• Subject Area: Hematology, Oncology ; Immunology ; Nuclear Medicine, Radiotherapy, Radiobiology ; Cell Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405993611

Brain metastasis (BrM) represents an unmet clinical need with high demand for novel and effective therapeutic strategies to improve treatment options and quality of life for BrM patients. Given the critical role of tumor-associated stromal and immune cells in disease progression, benefits of tumor microenvironment (TME)-targeted therapies are increasingly recognized and strategies that block tumor-promoting functions or support anti-tumor immunity are emerging. The TME in BrM is characterized by high myeloid cell content and low to moderate T cell infiltration depending on the primary tumor entity. Therapeutic efficacy of T cell-directed immunotherapy is often blunted by the strong immune suppressive milieu in BrM predominantly mediated by monocyte-derived macrophages. Transcriptomic analyses revealed an induction of components of the purinome in immune and tumor cells in BrM suggesting a critical role of adenosinergic signaling in immune suppression and T cell exhaustion. We employed genetic and pharmacological strategies to target different components of the purinome to convert adenosine-mediated immune-suppression into purine-driven inflammation thereby creating an environment for effective T cell reactivation in BrM. Our data confirmed a central role of adenosinergic signaling in suppressing anti-tumor immune responses in BrM. This effect could be revoked by pharmacological inhibition of the nucleotidases CD39 and CD73 as well as the adenosine receptor A2a. Additional application of whole brain radiotherapy (WBRT) further improved median survival, while the addition of aPD1 alone or in combination with WBRT did not show beneficial effects in the context of adenosinergic signaling blockade. Taken together, blockade of metabolic immune checkpoints combined with radiotherapy represents a promising strategy to control disease progression in BrM. However, additional insight is needed to further improve strategies for effective reactivation of T cell responses by immune checkpoint inhibition in the context of blockade of adenosinergic signaling. Here, we propose to perform detailed analyses how changes in the purinome modulate the immune status in BrM. We seek to translate these findings into improved intervention strategies with the aim to overcome tissue-specific resistance mechanisms that limit the efficacy of immunotherapy against BrM.

• DFG Programme: Research Grants