Sex-specific T cell exhaustion drives differential immune responses in glioblastoma

Abstract

Sex differences in glioblastoma (GBM) incidence and outcome are well recognized, and emerging evidence suggests that these extend to genetic/epigenetic and cellular differences, including immune responses. However, the mechanisms driving immunological sex differences are not fully understood. Using GBM models, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased T cell infiltration and increased T cell exhaustion. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD1 treatment. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, which was further corroborated by in vitro exhaustion assays. Moreover, increased T cell exhaustion was observed in male GBM patients. These findings demonstrate sex-specific pre-determined behavior of T cells is critical in inducing sex differences in GBM progression and immunotherapy response.Statement of significanceImmunotherapies in GBM patients have been unsuccessful due to a variety of factors including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-specific T cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve therapeutic efficacy of immunotherapy in GBM.

Sex-specific molecular differences in glioblastoma: assessing the clinical significance of genetic variants

“…Other studies have also found an increased CD4+, and in some cases, CD8+ T cell popular in female tumors ( 11 ). Furthermore, in a recent study, male CD8+ T cells infiltrating murine GBM tumors were found to express more inhibitory receptors—such as PD1, CTLA4, and LAG3—leading to a higher rate of T cell exhaustion than in females ( 40 ). Subsequent analysis showed that while male CD8+ T cells were enriched for the stem-like/progenitor exhausted (PEX) subtype (CD8 + CD44 + PD1 + TCF1 + TIM3 - ), female CD8+ T cells were enriched for the effector (EFF) subtype (CD8 + CD44 + TCF1 - TIM3 - ), and consequently, they produced more IFN- γ and TNF in response to stimuli ( 40 ).…”

“…Furthermore, in a recent study, male CD8+ T cells infiltrating murine GBM tumors were found to express more inhibitory receptors—such as PD1, CTLA4, and LAG3—leading to a higher rate of T cell exhaustion than in females ( 40 ). Subsequent analysis showed that while male CD8+ T cells were enriched for the stem-like/progenitor exhausted (PEX) subtype (CD8 + CD44 + PD1 + TCF1 + TIM3 - ), female CD8+ T cells were enriched for the effector (EFF) subtype (CD8 + CD44 + TCF1 - TIM3 - ), and consequently, they produced more IFN- γ and TNF in response to stimuli ( 40 ). Sex differences in myeloid-derived suppressor cells (MDSCs), immature myeloid cells that can suppress the immune response and work synergistically with cancer cells, between GBM patients have also been discovered ( 41 ).…”

Understanding the immunosuppressive microenvironment of glioma: mechanistic insights and clinical perspectives

“…KDM6B deficiency inhibits secretion of immunosuppressive mediators such as MAF BZIP transcription factor B (MAFB), suppressor of cytokine signaling 3 (SOCS3), and signal regulatory protein alpha (SIRPA), thereby enhancing the efficacy of anti-PD-1/programmed cell death 1 ligand 1 (PD-L1) therapy [52]. In humans, presence of X chromosome inactivation escape gene KDM6A [53] results in lower CD8 + T cell levels in male GBM microenvironments than in female GBM microenvironments [54]. Moreover, T cells in the male GBM microenvironment are more prone to exhaustion.…”

“…Modifying in epigenetic Impact on the immune microenvironment of GBM Reference IRF8 DNA Methylation Promote immune evasion and transformation of GBM into mesenchymal types [49] OLFML3 CLOCK mediated transcriptional upregulation Promote self-renewal of GSC and recruit TMAs [50] YY1 m6A modifying Promote Treg infiltration [51] KDM4A Demethylation of H3K9me3 Inhibit cell autophage [52] KDM6A Demethylation of H3K27me3 Promote CD8 + T cell exhaustion [54] KDM6B Demethylation of H3K27me3 Promote the immunosuppressive function of myeloid cells [63] IDH DNA Methylation Suppress CD3 + & CD8 + T cell infiltration [66] IFN-α BET & HDAC modifying Regulate the expression of ISG and PD-L1 [68] BRD4 Promote H3K27ac modifying Maintain immunosuppressive microenvironment [69] ALKBH5 m6A demethylation Recruite TAM [70] Integrin β1 Increased chromatin accessibility Recruite MDSC [71] EZH2 Promote H3K27me3 in the promoter of iNOS and TNFα Promote the formation of M2 type macrophage [72] IGFBP1 m6A modifying Sustain immunosuppressive microenvironment [73] IL-7 Methylation Promote immune evasion [74] CXCL9/10 H3K27me3 Suppress T cell recruitment [75] GPX7 DNA Methylation Inhibit innate immunity and adaptive immunity [76] MTAP DNA Methylation Suppress macrophage recruitment [77] MIR155HG Reduce methylation levels in promoter Suppress immunocell infiltration [78] FOXP3 Demethylation Affect the generation of Treg and CD4 + T cell [79,80] LSD1 Histone demethylase Inhibit p53 pathway [81] JMJD3 Histone demethylase Inhibit p53 pathway [82] KAT8 H4K16ac Promote the production of tumor-associated microglia [83] H3.3 G34R/V Regulate the cGAS/STING pathway [84] Lin et al Journal of Hematology & Oncology (2024) 17:31 and CD45RO + [87]. Through techniques such as spatial transcriptomics (ST) and single-cell RNA sequencing (scRNA-seq), it becomes evident that GBM cells could induce local environmental changes through signaling and structural alterations.…”

Systemic immune derangements are shared across various CNS pathologies and reflect novel mechanisms of immune privilege

“…Many studies have focused on T-cell exhaustion, 4 , 12–14 including both progenitor and terminal exhaustion, within the tumor microenvironment and recent studies underscore the role of biological sex in the development of exhausted T-cells within the tumor. 15 This review, however, will focus on peripheral immunosuppression. Both primary and metastatic brain tumors are difficult to treat with conventional therapies, as they display unique challenges including both intratumoral and peripheral immunosuppression.…”