Cross-Disease myeloid remodeling along the GMP-TAM axis predicts immunotherapy response in glioma.

[BACKGROUNDS] Immune checkpoint inhibitor-induced colitis (CICs) represents a state of systemic immune activation and is paradoxically associated with superior anti-tumor responses. This study has been designed to explore gene signatures derived from CICs that could identify the key immunological drivers, and predict sensitivity of immunotherapy in immunologically cold tumors e.g. glioma.

[METHODS] We integrated bulk, single-cell, and spatial transcriptomic data from CICs and glioma cohorts. Cross-disease analysis have been performed to identify an immunotherapy-responsive granulocyte-monocyte progenitor (IR-GMP) signature. Risk score (RS) model has been constructed through LASSO regression, and have been validated for its potential prognostic as well as predictive values.

[RESULTS] We have identified 112 IR-GMP genes enriched in pathways that may cause myeloid immunosuppression. A four-gene RS model (RAC2, LAPTM5, HCLS1, CD74) has been developed, and glioma patients have been divided into high- and low-risk groups based on the model. RS is an independent prognostic factor, and demonstrated to exhibit superior accuracy for predicting survival when combining with clinical variables. High-RS tumors exhibited immunosuppressive TME characterized by M2 macrophage enrichment, SPP1-signaling hyperactivation, and an immune-tolerant genomic landscape (C4 subtype). Crucially, the high-RS group showed significantly higher immunophenoscores under PD-1 and combined PD-1/CTLA-4 blockade, indicating potential sensitivity to immunotherapy, and distinct chemotherapy susceptibility. Single-cell and spatial transcriptomic results confirmed the lineage specificity and regional colocalization of RS genes with M2 macrophages.

[CONCLUSIONS] Our cross-disease analysis unveils a conserved GMP-TAM myeloid remodeling axis in glioma. The derived RS model may serve as a powerful marker for predicting prognosis, and also for predicting the benefits derived from immunotherapy, offering a novel tool for precision immunotherapy in glioma.