Dataset Information

Sex-Biased 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 immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tumor. Furthermore, a higher frequency of progenitor exhausted T cells was found in males, with improved responsiveness to anti-PD-1 treatment. Moreover, increased T-cell exhaustion was observed in male GBM patients. Bone marrow chimera and adoptive transfer models indicated that T cell-mediated tumor control was predominantly regulated in a cell-intrinsic manner, partially mediated by the X chromosome inactivation escape gene Kdm6a. These findings demonstrate that sex-biased predetermined behavior of T cells is critical for inducing sex differences in GBM progression and immunotherapy response.

Significance

Immunotherapies in patients with GBM have been unsuccessful due to a variety of factors, including the highly immunosuppressive tumor microenvironment in GBM. This study demonstrates that sex-biased T-cell behaviors are predominantly intrinsically regulated, further suggesting sex-specific approaches can be leveraged to potentially improve the therapeutic efficacy of immunotherapy in GBM. See related commentary by Alspach, p. 1966. This article is featured in Selected Articles from This Issue, p. 1949.

SUBMITTER: Lee J

PROVIDER: S-EPMC10481130 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Lee Juyeun J Nicosia Michael M Hong Ellen S ES Silver Daniel J DJ Li Cathy C Bayik Defne D Watson Dionysios C DC Lauko Adam A Kay Kristen E KE Wang Sabrina Z SZ Johnson Sadie S McGraw Mary M Grabowski Matthew M MM Kish Danielle D DD Desai Amar B AB Goodman Wendy A WA Cameron Scott J SJ Okada Hideho H Valujskikh Anna A Fairchild Robert L RL Ahluwalia Manmeet S MS Lathia Justin D JD

Cancer discovery 20230901 9

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 immunologic sex differences are not fully understood. Here, we demonstrate that T cells play a critical role in driving GBM sex differences. Male mice exhibited accelerated tumor growth, with decreased frequency and increased exhaustion of CD8+ T cells in the tu ...[more]

PMID: 37378557

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Project description:BackgroundMethylation-related signatures play crucial roles in tumorigenesis and progression. However, their roles in the immune response in primary glioblastoma (GBM) remains unclear.MethodsWe analyzed the differential expression of specific members of T cell exhaustion-related pathways in GBM from the perspective of T cell exhaustion. We further screened for significantly negatively correlated methylation sites as candidate methylation markers for T cell exhaustion. Using consensus clustering, we divided the samples into two categories with significant differences in overall survival (OS). We then performed univariate and multivariate Cox regression analyses to construct the T Cell Exhaustion Methylation (TEXM) signature. Finally, we confirmed that this signature served as an independent prognostic factor, and further characterized it in terms of drug resistance and immunotherapy.ResultsWe identified 95 significantly differentially expressed T cell exhaustion-related genes and 51 methylation markers associated with T cell exhaustion. The cancer samples were classified according to methylation site markers, thus indicating two subtypes with significant differences in OS: subtype A and subtype B. Tumor scores, stromal scores, tumor purity, and ESTIMATE scores all showed significant differences between subtypes (P < 0.05). Univariate Cox regression analysis identified five methylation sites significantly associated with OS, and multivariate Cox regression analysis was used to construct the TEXM signature model by using these five methylation sites. Significant differences in OS were found between the groups with high and low TEXM signature scores, on the basis of calculation of the TEXM signature scores of tumor samples and using the median score to divide them into high and low score groups. Survival analysis revealed that the high score group had poorer OS and DFS than the low score group in the validation set. Notably, we observed a significant difference in drug sensitivity between the high and low TEXM signature score groups, with the high score group showing higher drug resistance and poorer prognosis. The tumor immune state, as predicted with Tracking Tumor Immunophenotype (TIP), revealed significant differences in antitumor immune scores between the high and low TEXM signature score groups. Finally, we identified 43 significantly differentially regulated metabolism-associated biological processes.ConclusionThe epigenetic methylation-related TEXM signature plays a key role in driving differential immune responses in GBM.

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Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

Significance

Publications

Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma.

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