| Sumario: | Simple Summary: This scientific study focuses on glioblastoma, a highly aggressive cancer with a poor prognosis. Despite various treatment modalities, including immune checkpoint inhibitors (ICBs), the efficacy of ICBs remains limited, prompting the need for a proactive approach to understand treatment response and resistance. This study involves a thorough analysis of two glioblastoma patient cohorts treated with the Programmed Cell Death Protein 1 (PD-1) blockade. Notably, 60% of the patients exhibited persistent disease progression despite the ICBs. We characterized the immune profiles of these patients with continued cancer progression, revealing multiple defects such as compromised macrophage, monocyte, and T follicular helper responses, impaired antigen presentation, abnormal regulatory T cell (Tregs) responses, and increased expression of immunosuppressive molecules. Using machine learning algorithms, we developed predictive models and software. This computational tool achieved significant success, accurately predicting the progression status of 82.82% of the glioblastoma patients in this study following ICBs based on their unique immune characteristics. In conclusion, this study proposes a personalized approach to immunotherapy in glioblastoma patients. By utilizing patient-specific attributes and computational predictions, we advocate for a paradigm shift towards tailored therapies. This approach has the potential to improve glioblastoma management, offering new possibilities for improved patient care following immunotherapy. Glioblastoma is a highly aggressive cancer associated with a dismal prognosis, with a mere 5% of patients surviving beyond five years post diagnosis. Current therapeutic modalities encompass surgical intervention, radiotherapy, chemotherapy, and immune checkpoint inhibitors (ICBs). However, the efficacy of ICBs remains limited in glioblastoma patients, necessitating a proactive approach to anticipate treatment response and resistance. In this comprehensive study, we conducted a rigorous analysis involving two distinct glioblastoma patient cohorts subjected to PD-1 blockade treatments. Our investigation revealed that a significant portion (60%) of patients exhibit persistent disease progression despite ICB intervention. To elucidate the underpinnings of resistance, we characterized the immune profiles of glioblastoma patients with continued cancer progression following anti-PD1 therapy. These profiles revealed multifaceted defects, encompassing compromised macrophage, monocyte, and T follicular helper responses, impaired antigen presentation, aberrant regulatory T cell (Tregs) responses, and heightened expression of immunosuppressive molecules (TGFB, IL2RA, and CD276). Building upon these resistance profiles, we leveraged cutting-edge machine learning algorithms to develop predictive models and accompanying software. This innovative computational tool achieved remarkable success, accurately forecasting the progression status of 82.82% of the glioblastoma patients in our study following ICBs, based on their unique immune characteristics. In conclusion, our pioneering approach advocates for the personalization of immunotherapy in glioblastoma patients. By harnessing patient-specific attributes and computational predictions, we offer a promising avenue for the enhancement of clinical outcomes in the realm of immunotherapy. This paradigm shift towards tailored therapies underscores the potential to revolutionize the management of glioblastoma, opening new horizons for improved patient care.
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