American Association for Cancer Research
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Supplementary Figures S1-S16 from Sex-Biased T-cell Exhaustion Drives Differential Immune Responses in Glioblastoma

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posted on 2023-09-06, 17:32 authored by Juyeun Lee, Michael Nicosia, Ellen S. Hong, Daniel J. Silver, Cathy Li, Defne Bayik, Dionysios C. Watson, Adam Lauko, Kristen E. Kay, Sabrina Z. Wang, Sadie Johnson, Mary McGraw, Matthew M. Grabowski, Danielle D. Kish, Amar B. Desai, Wendy A. Goodman, Scott J. Cameron, Hideho Okada, Anna Valujskikh, Robert L. Fairchild, Manmeet S. Ahluwalia, Justin D. Lathia

Supplementary Fig. S1. Immune cell-dependent survival differences between males and females in murine glioblastoma models. Supplementary Fig. S2. Mouse syngeneic GBM cell lines do not contain a Y chromosome. Supplementary Fig. S3. Frequencies of tumor-infiltrating immune cells in SB28 model. Supplementary Fig. S4. Sex difference in survival in SB28-OVA model and GL261 model. Supplementary Fig. S5. No sex difference in T cells was observed at an earlier time point. Supplementary Fig. S6. Male T cells are more exhausted in the GL261 model. Supplementary Fig. S7. Phenotype of T cells in the periphery does not replicate the sex differences shown in tumor-infiltrating T cells. Supplementary Fig. S8. Frequencies of exhausted T cell subsets. Supplementary Fig. S9. PD1 blockade enhanced immune responses Supplementary Fig. S10. No significant difference in the immune cell composition of bone marrow chimera mice before tumor implantation. Supplementary Fig. S11. Male and female CD8+ T cells in mixed bone marrow chimera model. Supplementary Fig. S12. Phenotyping tumor-infiltrating CD8+ T cell from GBM patient tumors. Supplementary Fig. S13. scRNA-seq analysis of tumor-infiltrating CD8+ T cells from GBM patients. Supplementary Fig. S14. mRNA expression level of transcription factors in human in vitro exhausted T cells. Supplementary Fig. S15. Expression level of X chromosome inactivation (XCI) genes in exhausted T cells. Supplementary Fig. S16. Inhibition of UTX abrogates sex differences in T cell exhaustion.


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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. 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

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