Dottorato in NETWORK ONCOLOGY AND PRECISION MEDICINE

Titolo della tesi: Immune receptor CD137 as a biomarker in solid tumors and potential immunotherapeutic target in glioblastoma

Background: Glioblastoma (GBM) is one of the most threatening tumors in adults. GBM treatment faces challenges in enhancing patient survival and expanding therapeutic possibilities, especially considering the compromised state of the immune system in this "immunologically privileged" tumor. Understanding the unique immune dynamics within GBM is crucial for tailoring effective therapies. Aim: The objective of this study is to investigate the role of the immune co-receptor CD137 as biomarker of response to immunotherapy in patients with solid tumors and elucidate its potential role as a biomarker and therapeutic target in GBM. The research investigates the expression of CD137 within distinct circulating T cell subsets in various solid tumors in human patients treated with anti-PD1 agents to identify and validate its role as immune biomarker. Moreover, the research investigates the expression of CD137 in different T-cell subsets within the GBM microenvironment, exploring the complex relationship among CD137, T-cell exhaustion, immunosuppression, and immunotherapy responsiveness. Lastly, these findings may be translated into a novel therapeutic approach to improve the immune response against GBM. Results: Through investigations in various solid tumors in human patients treated with anti-PD1 immunotherapy, we identified and validated circulating CD137 on CD8+ T cells as a predictive biomarker of response to treatment. Subsequently, the study focused on GBM, delving into CD137’s role in the anti-tumor immune response in human patients and murine models. In GBM patients, higher levels of infiltrated CD137+CD8+PD1+ T cells were negatively correlated with survival after surgery. Particularly, CD137 is more expressed in terminally exhausted T cells compared with progenitor ones, both in humans and mice. Hence, mice models treated with anti-CD137 showed an increase in T-cell activation and exhaustion inside the tumor and in the spleen, accompanied by augmented cytokine secretion within the tumor microenvironment. The study also explored the impact of hypoxia, a key factor in GBM immunosuppression, on T-cell exhaustion and tumor associated macrophages (TAM). Axitinib, a VEGFR-targeting TKI, was utilized to reduce the hypoxia-induced immunosuppression, and the targeting CD137 combination with axitinib resulted in increased overall survival and activation of lasting immunological memory as tested in brain tumor mouse model. Conclusion: CD137 could represent a promising biomarker for immunotherapy response in solid tumors, including glioblastoma where immunotherapy fails. CD137 appears to play an important role in the biological process of exhaustion of T cells in GBM. CD137 targeting combined with modulation of the tumor microenvironment represents a promising strategy to overcome the challenges associated with GBM immune unresponsiveness, providing new prospective for more effective and personalized immunotherapeutic treatments in GBM.