Identifying New Tumour Microenvironment Contexts of Vulnerability in Glioblastoma
Creators: name: White, Kieron
Publisher: name: Royal College of Surgeons in Ireland
Year: 2024
Subjects: classificationCode: 321199
subject: Oncology and carcinogenesis not elsewhere classified

description: New precision medicine therapies are urgently required for isocitrate dehydrogenase wild-type (IDH-wt) glioblastoma (GBM). Nevertheless, efforts to subtype patients based on molecular profiles have thus far failed to direct treatment strategies. We hypothesized that specific interrogation of the tumor microenvironment (TME) and identification of new TME specific subtypes may guide new therapeutic directions.
To this end, we first validated the microenvironment cell population (MCP)- counter method for use in the brain tumor setting by multiplex- immunohistochemistry. Using this method, we classified the GLIOTRAIN (www.gliotrain.eu) IDH-wt GBM cohort (N=123) into 3 novel clusters characterised by differences in TME-composition and subsequently validated findings in the Cancer Genome Atlas (TCGA) (N=69), Chinese Glioma Genome Atlas (CGGA) (N=72) and Duke University (DUKE) (N=162) cohorts. A TME<sup>High</sup> group (37%) was characterized by elevated lymphocytes, myeloid cells and immune checkpoint genes: PDCD1(PD1) and CTLA4. Moreover, tertiary lymphoid structures (TLS) were a feature of TME<sup>High</sup>/mesenchymal<sup>+ </sup>patients. TME<sup>Med</sup> tumours (38%) were enriched for endothelial cells (P=0.00095), heterogeneous immune population and neuronal signalling. The TME<sup>Low</sup> cohort (25%) represented an ‘immune-desert’ group and harbouring epidermal growth factor receptor (<em>EGFR)</em> mutations. Extrachromosomal (ec)DNA Platelet Derived Growth Factor Receptor Alpha (<em>CDK4)</em> amplifications were a common feature of TMELow. Mutational analysis revealed that samples with <em>EGFR</em> mutations and Cyclin-Dependent Kinase Inhibitor 2A (<em>CDKN2A)</em> alterations presented significantly decreased immune cell populations. Longitudinal analysis within the The Glioma Longitudinal AnalySiS (GLASS) cohort revealed a TME-subtype transition (TME<sup>Med</sup> to TME<sup>High</sup>) upon recurrence (21% GLASS cohort), influenced by a significant increase in the monocytic-lineage signature. Finally, assessment of the GBM immunotherapy clinical trial datasets revealed that TMEHigh patients treated with neoadjuvant anti-PD1 have a significantly increased overall survival compared to non-TMEHigh patients treated with neoadjuvant anti-<em>PD1</em> and patients treated in the adjuvant setting (P=0.04). Moreover, TME<sup>High</sup> patients treated with anti-PD1 and an oncolytic virus (PVSRIPO) in the adjuvant setting, showed a trend towards improved survival compared to TME<sup>Med</sup> and TME<sup>Low</sup> (P=0.15 and P=0.056 respectively).
Overall, we have identified a new TME-based classification system for IDH-wt GBM. This system may be used to better inform a precision targeting approach in this disease setting. For example, we hypothesise that patients bearing TME<sup>Low</sup> tumours may be amenable to neoadjuvant anti-T cell immunoglobulin and mucin- domain containing-3 (<em>TIM3</em>) + <em>EGFR</em> inhibitor, TME<sup>Med</sup> to anti-angiogenic immunotherapy and TME<sup>H</sup><sup>igh</sup> to neoadjuvant anti-PD1 + adjuvant Colony Stimulating Factor 1 Receptor (<em>CSF1R</em>) inhibition.