Spatial transcriptomic analysis reveals lack of response to PD-1 blockade in recurrent glioblastoma

Area of Science:

• Oncology
• Immunotherapy
• Genomics

Background:

• Immune checkpoint inhibitors, particularly PD-1 blockade, have revolutionized cancer treatment.
• However, clinical trials of PD-1 blockade in glioblastoma (GBM) have yielded limited therapeutic benefits.
• Previous studies reported inconsistent transcriptional changes in T cells post-treatment.

Purpose of the Study:

• To investigate the effects of PD-1 blockade on tumor cells and tumor-associated macrophages (TAMs) in recurrent GBM.
• To analyze transcriptional changes in response to neoadjuvant nivolumab using spatial transcriptomics.

Main Methods:

• Digital Spatial Profiling (GeoMx, NanoString) was employed on formalin-fixed paraffin-embedded (FFPE) tumor samples from 26 patients with matched primary and recurrent IDH-wildtype GBM.
• Samples included 16 patients who received neoadjuvant nivolumab.
• Transcriptomic profiles of tumor (SOX2⁺) and TAM (IBA1⁺) segments were compared between treated and untreated recurrent tumors.

Main Results:

• PD-1 blockade with nivolumab did not induce significant gene expression changes in glioblastoma tumor cells or TAMs.
• No substantial differences were observed in global expression profiles, malignant cell states, cell cycle activity, interferon signaling, or myeloid transcriptional programs.
• Spatial transcriptomic analysis revealed no measurable response in tumor cells or TAMs following neoadjuvant PD-1 blockade.

Conclusions:

• Neoadjuvant PD-1 blockade does not elicit detectable transcriptomic responses in tumor cells or TAMs in recurrent GBM.
• These findings correlate with the observed lack of clinical efficacy of PD-1 inhibitors in GBM.
• Alternative strategies are needed to enhance immunotherapy outcomes in glioblastoma.