526P - In silico evaluation of the mutational profile of glioblastomas with high expression of PD1, CTLA4 and LAG3 identifies the ERBB-PI3K pathway as a druggable vulnerability target

Background

Glioblastoma (GBM) is a major therapeutic challenge. Genomic studies have helped to decipher the molecular landscape of commonly deregulated genes in GBM. Unfortunately, approved immune checkpoint inhibitors, such as anti PD1, anti LAG3 and antiCTLA4 agents, have not shown clinical activity in GBM. In this study we explore the mutational profile of tumors with high expression of PD1, LAG3 and CTLA-4, to identify potential druggable vulnerabilities.

Methods

We interrogated TCGA with data from 528 patients. We explored the mutational profile of tumors with high expression of PD1, LAG3 and CTLA4 to explore the associations between the selected mutated genes and immune infiltration using TIMER2.0. Gene Ontology Biological processes related to each gene were explored with the EnrichR platform. Protein expression was evaluated using the Human Surfaceome Atlas.

Results

We selected 82 (15,53%) patients that had high hPDCD1 expression, 84 (15,9%) with elevated hLAG3 levels, and 70 (13,25%) with high hCTLA4. Among the total number of mutated genes in each subgroup we selected only those expressed in > 5% of the patients. As a result, we identified 23 mutated genes in the hPDCD1 subgroup, 66 in the hLAG3 and 69 in the hCTLA4 group. Genes highly mutated in the three subgroups included: TP53 24-30%, EGFR 20-37%, PTEN 15-30%, TTN 24-28% and MUC16 17-20%. This set of genes represented 21% of patients in the hPDCD1 group, 7,57% in hLAG3 and 7,24% in the hCTLA4 group. 21 mutated genes in the hPDCD1 group were shared with the other groups, 13 genes in the hCTLA4 and hLAG3 groups, and only one gene was commonly mutated between hPDCD1 and hLAG3, and between hPDCD1 and hCTLA4 tumors. These frequently mutated genes correlated with the expression of gamma-delta T cells (30% in hPDCD1, 35% in hLAG3 and up to 26% in hCTLA4). Gene set enrichment analysis included: PIK3 and ERBB2 signaling pathway, ion channel activity, protease/phosphatase binding, or C-X3-C chemokine binding.

Conclusions

GBM with high expression of PD1, CTLA4 and LAG3 display frequent mutations in the ERBB-PI3K signaling pathway including EGFR and PTEN. These genes correlated with presence of gamma-delta T cells in tumor infiltrates.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.