Munich Cluster for Systems Neurology
print


Breadcrumb Navigation


Content

The glioblastoma multiforme tumor site promotes the commitment of tumor-infiltrating lymphocytes to the TH17 lineage in humans.

Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2206208119. doi: 10.1073/pnas.2206208119. Epub 2022 Aug 15. PMID: 35969754.

Authors/Editors: Mitsdoerffer M, Aly L, Barz M, Engleitner T, Sie C, Delbridge C, Lepennetier G, Öllinger R, Pfaller M, Wiestler B, Rad R, Meyer B, Knier B, Schmidt-Graf F, Gempt J, Korn T.
Publication Date: 2022

Significance

Glioblastoma multiforme (GBM) has been impervious to immune interventional therapies. Here, we analyzed the transcriptome of highly pure CD4+ and CD8+ T cells from the tumor bed, normal-appearing brain tissue, and peripheral blood of treatment-naive GBM patients. While the transcriptome of tumor-infiltrating CD8+ T cells was consistent with a potentially robust antitumor response, tumor-infiltrating CD4+ T cells showed a strong commitment to the TH17 lineage. Since intratumoral TH17 cells might exert a dominant-negative function as to a productive antitumor response, our data suggest that a site-directed anti-TH17 intervention may be a prerequisite for efficient antitumor immunity in GBM.

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 (TH17) 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 TH17 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-TH17 cell interventions needs to be further investigated.

08_mitsdoerfer

Related Links