The combination of neoantigen quality and T lymphocyte infiltrates identifies glioblastomas with the longest survival

Abstract

Glioblastoma (GBM) is resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with better survival and response to immunotherapies in selected solid tumors but how neoantigens impact clinical outcome in GBM remains unclear. Here, we exploit the similarity between tumor neoantigens and infectious disease-derived immune epitopes and apply a neoantigen fitness model for identifying high-quality neoantigens in a human pan-glioma dataset. We find that the neoantigen quality fitness model stratifies GBM patients with more favorable clinical outcome and, together with CD8 + T lymphocytes tumor infiltration, identifies a GBM subgroup with the longest survival, which displays distinct genomic and transcriptomic features. Conversely, neither tumor neoantigen burden from a quantitative model nor the isolated enrichment of CD8 + T lymphocytes were able to predict survival of GBM patients. This approach may guide optimal stratification of GBM patients for maximum response to immunotherapy.

Tumor fitness, immune exhaustion and clinical outcomes: impact of immune checkpoint inhibitors

“…Overall our study indicates that while tumor fitness scores can be used to predict response to checkpoint inhibitors, these measures do not seem to predict survival in patients not treated with checkpoint inhibitors where endogenous immune activation is a significant survival factor. It is important to note that while this tumor fitness measure and its underlying assumptions have been adapted with positive predictive results in other contexts (24,25), we find that the exact form of the model is not predictive in these endogenous cases. Nevertheless, it is encouraging to observe that CYT measures are powerful in both treated and untreated patients, which may point to the existence of universally predictive and prognostic immune activation signatures.…”

A MAP of tumor-host interactions in glioma at single cell resolution

“…Recent trials have shown that endogenous T cells play a significant role in the prolonged survival time of glioma patients (Brown et al, 2016; Zhang et al, 2019). However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immune-mediated antitumor response.…”

“…The interaction between malignant cells and their microenvironment is critical for both normal tissue homeostasis and tumor growth, as the immune system can eliminate cancer cells that present neoantigens recognized by receptors of the adaptive immune system or express ligands for activating receptors on innate immune cells (Schreiber et al, 2011). The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms (Bedognetti et al, 2016; Joyce and Fearon, 2015; Zhang et al, 2019) and influences the response to immune therapies (Ceccarelli et al, 2016; Cristescu et al, 2018). Therefore, the elucidation of the tumor-host interaction mechanisms plays a crucial role in the understanding of the tumor growth and evolution (Angelova et al, 2018; Bedognetti et al, 2019) and for the identification immuno-oncology therapeutic targets (Hoos, 2016).…”

“…Immune checkpoint inhibitor (ICI) therapies are aimed to targeting the specific cell-cell interaction between PD1 and PD-L1 or CTLA4 and B7-1/B7-2 (Pardoll, 2012). The identification of novel interactions that characterize tumor-types and shape the immune response has also important clinical implications can also help to better stratify patients (Zhang et al, 2019) and predict response to ICI (Roelands et al, 2019).…”

“…In particular Glioblastoma (grade IV glioma) is the most frequent type of primary brain tumor being an invariably lethal tumor type with median survival below 15 months (Stupp et al, 2005). In glioma, higher mutational load is associated with increased tumor aggressiveness (Zhang et al, 2019). The tumor microenvironment of GBM is dominated by myeloid-derived cells, mostly blood-derived macrophages and resident microglia (Quail and Joyce, 2017; Wang et al, 2018; Yuan et al, 2018), hampering a productive anti-tumor immunity in GBM and excluding T lymphocytes and (Hussain et al, 2006).…”