An In Silico Glioblastoma Microenvironment Model Dissects the Immunological Mechanisms of Resistance to PD-1 Checkpoint Blockade Immunotherapy

The PD-1 immune checkpoint-based therapy has emerged as a promising therapy strategy for treating the malignant brain tumor glioblastoma (GBM). However, patient response varies in clinical trials due in large to the tumor heterogeneity and immunological resistance in the tumor microenvironment. To further understand how mechanistically the niche interplay and competition drive anti-PD-1 resistance, we established an in-silico model to quantitatively describe the biological rationale of critical GBM-immune interactions, such as tumor growth and apoptosis, T cell activation and cytotoxicity, and tumor-associated macrophage (TAM) mediated immunosuppression. Such an in-silico experimentation and predictive model, based on the in vitro microfluidic chip-measured end-point data and patient-specific immunological characteristics, allowed for a comprehensive and dynamic analysis of multiple TAM-associated immunosuppression mechanisms against the anti-PD-1 immunotherapy. Our computational model demonstrated that the TAM-associated immunosuppression varied in severity across different GBM subtypes, which resulted in distinct tumor responses. Our prediction results indicated that a combination therapy co-targeting of PD-1 checkpoint and TAM-associated CSF-1R signaling could enhance the immune responses of GBM patients, especially those patients with mesenchymal GBM who are irresponsive to the single anti-PD-1 therapy. The development of a patient-specific in silico-in vitro GBM model would help navigate and personalize immunotherapies for GBM patients.