The glioblastoma multiforme tumor site promotes the commitment of tumor-infiltrating lymphocytes to the T_H17 lineage in humans.

Abstract

Although glioblastoma multiforme (GBM) is not an invariably cold tumor, checkpoint inhibition has largely failed in GBM. In order to investigate T cell-intrinsic properties that contribute to the resistance of GBM to endogenous or therapeutically enhanced adaptive immune responses, we sorted CD4⁺ and CD8⁺ T cells from the peripheral blood, normal-appearing brain tissue, and tumor bed of nine treatment-naive patients with GBM. Bulk RNA sequencing of highly pure T cell populations from these different compartments was used to obtain deep transcriptomes of tumor-infiltrating T cells (TILs). While the transcriptome of CD8⁺ TILs suggested that they were partly locked in a dysfunctional state, CD4⁺ TILs showed a robust commitment to the type 17 T helper cell (T_H17) lineage, which was corroborated by flow cytometry in four additional GBM cases. Therefore, our study illustrates that the brain tumor environment in GBM might instruct T_H17 commitment of infiltrating T helper cells. Whether these properties of CD4⁺ TILs facilitate a tumor-promoting milieu and thus could be a target for adjuvant anti-T_H17 cell interventions needs to be further investigated.