B-cells Drive Response to PD-1 Blockade in Glioblastoma Upon Neutralization of TGFß-mediated Immunosuppression.

Immunotherapy has revolutionized cancer treatment but has yet to be translated into brain tumors. Studies in other solid tumors suggest a central role of B-cell immunity in driving immune-checkpoint-blockade efficacy. Using single-cell and single-nuclei transcriptomics of human glioblastoma and melanoma brain metastasis, we found that tumor-associated B-cells have high expression of checkpoint molecules, known to block B-cell-receptor downstream effector function such as plasmablast differentiation and antigen-presentation. We also identified TGFß-1/TGFß receptor-2 interaction as a crucial modulator of B-cell suppression. Treatment of glioblastoma patients with pembrolizumab induced expression of B-cell checkpoint molecules and TGFß-receptor-2. Abrogation of TGFß using different conditional knockouts expanded germinal-center-like intratumoral B-cells, enhancing immune-checkpoint-blockade efficacy. Finally, blocking αVß8 integrin (which controls the release of active TGFß) and PD-1 significantly increased B-cell-dependent animal survival and immunological memory. Our study highlights the importance of intratumoral B-cell immunity and a remodeled approach to boost the effects of immunotherapy against brain tumors.

The Interplay between Glioblastoma and Its Microenvironment.

GBM is the most common primary brain tumor in adults, and the aggressive nature of this tumor contributes to its extremely poor prognosis. Over the years, the heterogeneous and adaptive nature of GBM has been highlighted as a major contributor to the poor efficacy of many treatments including various immunotherapies. The major challenge lies in understanding and manipulating the complex interplay among the different components within the tumor microenvironment (TME). This interplay varies not only by the type of cells interacting but also by their spatial distribution with the TME. This review highlights the various immune and non-immune components of the tumor microenvironment and their consequences f the efficacy of immunotherapies. Understanding the independent and interdependent aspects of the various sub-populations encapsulated by the immune and non-immune components will allow for more targeted therapies. Meanwhile, understanding how the TME creates and responds to different environmental pressures such as hypoxia may allow for other multimodal approaches in the treatment of GBM. Ultimately, a better understanding of the GBM TME will aid in the development and advancement of more effective treatments and in improving patient outcomes.

Current Immunotherapeutic Strategies for the Treatment of Glioblastoma.

Glioblastoma (GBM) is a lethal primary brain tumor. Despite extensive effort in basic, translational, and clinical research, the treatment outcomes for patients with GBM are virtually unchanged over the past 15 years. GBM is one of the most immunologically "cold" tumors, in which cytotoxic T-cell infiltration is minimal, and myeloid infiltration predominates. This is due to the profound immunosuppressive nature of GBM, a tumor microenvironment that is metabolically challenging for immune cells, and the low mutational burden of GBMs. Together, these GBM characteristics contribute to the poor results obtained from immunotherapy. However, as indicated by an ongoing and expanding number of clinical trials, and despite the mostly disappointing results to date, immunotherapy remains a conceptually attractive approach for treating GBM. Checkpoint inhibitors, various vaccination strategies, and CAR T-cell therapy serve as some of the most investigated immunotherapeutic strategies. This review article aims to provide a general overview of the current state of glioblastoma immunotherapy. Information was compiled through a literature search conducted on PubMed and clinical trials between 1961 to 2021.

Correlation of post-contrast T1-weighted MRI surface regularity, tumor bulk, and necrotic volume with Ki67 and p53 in glioblastomas.

PURPOSE: p53 and Ki67 status can be relevant to the management of glioblastoma. The goal of this study is to determine whether tumor morphology and bulk depicted on MRI correlate with p53 and Ki67 in glioblastoma. METHODS: A retrospective review of 223 patients with glioblastoma and corresponding p53 or Ki67 status, along with T1-weighted post-contrast MR images was performed. Enhancing tumors were outlined for determining surface regularity, tumor bulk, and necrotic volume. The median value of 0.1 was chosen for p53 and 0.2 for Ki67 to separate each data set into two classes. T tests and receiver operating characteristic analysis were performed to determine the separation of the classes and the predicting power of each feature. RESULTS: There were significant differences between tumor surface regularity (p = 0.01) and necrotic volume (p = 0.0429) according to Ki67 levels, although neither had statistically significant predictive power (AUC = 0.697, p = 0.0506 and AUC = 0.577, p = 0.164, respectively). There were also significant differences between tumor bulk (p = 0.0239) and necrotic volume (p = 0.0200) according to p53 levels, but again no significant predictive power was found using ROC analysis (AUC = 0.5882, p = 0.0894 and AUC = 0.567, p = 0.155, respectively). CONCLUSION: Quantitative morphological tumor characteristics on post-contrast T1-weighted MRI can to a certain degree provide insights regarding Ki67 and p53 status in patients with glioblastoma.