A Spatial Multi-Omic Framework Identifies Gliomas Permissive to TIL Expansion.

Area of Science:

• Immunology
• Oncology
• Genomics

Background:

• Tumor-infiltrating lymphocyte (TIL) therapy shows promise for cancer treatment but faces challenges in 'cold' tumors like glioblastoma due to limited T cell infiltration and a suppressive microenvironment.
• Identifying factors that enable TIL expansion is crucial for broadening the application of this cell-based immunotherapy.

Purpose of the Study:

• To determine the genomic and spatial characteristics associated with the successful expansion of tumor-infiltrating lymphocytes (TILs) in high-grade gliomas.
• To establish a platform for selecting patients likely to benefit from TIL therapy in glioblastoma.

Main Methods:

• Integrated multimodal profiling of high-grade gliomas, including spectral flow cytometry, TCR sequencing, single-cell RNA-seq, Xenium in situ transcriptomics, and CODEX spatial proteomics.
• Comparative analysis of tumors with (TIL+) and without (TIL-) successful TIL generation.

Main Results:

• Successful TIL expansion was associated with IL7R expression, perivascular immune cell clustering, and tumor-specific metabolic programs (e.g., ACSS3).
• Tumors lacking TIL expansion (TIL-) were characterized by neuronal lineage signatures, immunosuppressive transcripts (TOX, FERMT1), and tumor-associated macrophages.

Conclusions:

• This study defines key molecular and spatial correlates of TIL manufacturing success in glioblastoma.
• The findings support a genomics-enabled selection strategy for adoptive T cell therapy and are being prospectively evaluated in the GIANT clinical trial (NCT06816927).