An endogenous glucocorticoid-cytokine signaling circuit promotes CD8<sup>+</sup>T cell dysfunction in the tumor microenvironment

Acharya, Nandini; Madi, Asaf; Zhang, H; Klapholz, Max; Christian, Elena; Ko, Dixon; Fell, Geoffrey; Tooley, Katherine; Mangani, Davide; Ji, Xia; Singer, Mervyn; Neuberg, Donna; Rozenblatt-Rosen, Orit; Regev, Aviv; Kuchroo, Vijay; Ac, Anderson

doi:10.1101/799759

Cited by 2 publications

(2 citation statements)

References 66 publications

(77 reference statements)

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“…Therefore, corticosteroid treatment during immune checkpoint blockade may impact the response to low affinity tumor antigens by suppressing fatty acid metabolism of these cells. Notably, it was recently shown that glucocorticoids are synthesized locally in tumor microenvironments by various cell types including myeloid lineages, macrophages and T cells themselves, meaning that their effects on T cell metabolism and function may be particularly relevant in the context of solid tumors ( 158 , 159 ) ( Table 1 ).…”

Section: Steroid Hormonesmentioning

confidence: 99%

Control of T Cell Metabolism by Cytokines and Hormones

2021

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Dynamic, coordinated changes in metabolic pathway activity underpin the protective and inflammatory activity of T cells, through provision of energy and biosynthetic precursors for effector functions, as well as direct effects of metabolic enzymes, intermediates and end-products on signaling pathways and transcriptional mechanisms. Consequently, it has become increasingly clear that the metabolic status of the tissue microenvironment directly influences T cell activity, with changes in nutrient and/or metabolite abundance leading to dysfunctional T cell metabolism and interlinked immune function. Emerging evidence now indicates that additional signals are integrated by T cells to determine their overall metabolic phenotype, including those arising from interaction with cytokines and hormones in their environment. The impact of these on T cell metabolism, the mechanisms involved and the pathological implications are discussed in this review article.

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Section: Steroid Hormonesmentioning

confidence: 99%

Control of T Cell Metabolism by Cytokines and Hormones

2021

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“…As such, future work is necessary to disentangle the molecular circuitry of androgen, Tcf1 and type I IFN. In this regard, there exists significant precedent for the involvement of Nuclear Receptor family members, including NR4A 46–49 and NR3C1 (glucocorticoid receptor) 50 , in CD8 + T cell exhaustion. Finally, our work showing sex specific CD8 + TIL behavior in bladder cancer highlights the broader opportunities for discovery due to sex disparities in health and disease.…”

Section: Discussionmentioning

confidence: 99%

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

Kwon¹,

Chung²,

Kaneko³

et al. 2020

Preprint

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Disclosure of Potential Conflicts of Interest: No potential conflicts of interest were disclosed. 24Abstract: Men and women show striking yet unexplained discrepancies in 25 incidence, clinical presentation, and therapeutic response across different types of 26 infectious/autoimmune diseases and malignancies 1,2 . For instance, bladder cancer 27 shows a 4-fold male-biased incidence that persists after adjustment for known risk 28 factors 3,4 . Here, we utilize murine bladder cancer models to establish that male-biased 29 tumor burden is driven by sex differences in endogenous T cell immunity. Notably, sex 30 differences exist in early fate decisions by intratumoral CD8 + T cells following their 31 activation. While female CD8 + T cells retain their effector function, male counterparts 32 readily adopt a Tcf1 low Tim3progenitor state that becomes exhausted over tumor 33 progression. Human cancers show an analogous male-biased frequency of exhausted 34 CD8 + T cells. Mechanistically, we describe an opposing interplay between CD8 + T cell 35 intrinsic androgen and type I interferon 5,6 signaling in Tcf1/Tcf7 regulation and formation 36 of the progenitor exhausted T cell subset. Consistent with female-biased interferon 37 response 7 , testosterone-dependent stimulation of Tcf1/Tcf7 and resistance to interferon 38 occurs to a greater magnitude in male CD8 + T cells. Male-biased predisposition for CD8 + 39T cell exhaustion suggests that spontaneous rejection of early immunogenic bladder 40 tumors is less common in males and carries implications for therapeutic efficacy of 41 immune checkpoint inhibitors 8,9 . 42Main: Sex is a biological variable with significant influence on immune function 1 . 43However, mechanisms underlying sex-biased incidence and mortality of various cancers 44 arising in non-reproductive organs remain elusive 2 . Indeed, bladder cancer shows a 4-45 fold male-biased incidence globally, which cannot be explained by established risk 46 factors: smoking, exposure to occupational hazards and urinary tract infection 3,4 . Here, 48 largely mediated by sex differences in T cell immunity. Flow cytometric and single cell 49 RNA-seq analyses of CD8 + tumor-infiltrating leukocytes (TILs) identified a striking male 50 bias in the formation of Tcf1 low Tim3progenitor cells 10 and in their transition to a 51 hypofunctional Tcf1 -Tim3 + exhausted state upon prolonged stimulation. In particular, 52androgen signaling was enriched in the progenitor exhausted subset. We found that 53 testosterone-induced Tcf1, an early molecular orchestrator of an exhaustion-associated 54 transcriptional landscape 11 in male CD8 + T cells, is also more resistant to pertinent 55 repression by female-biased type I interferon signaling 5 . Collectively, these findings 56 highlight sex differences in intratumoral CD8 + T cell fate as a potential mechanism 57 underlying bladder cancer sex bias and identify androgen as a possible target to modulate 58 CD8 + TIL exhaustion. 59CD8 + T cell immunity is required for sex differences in murine...

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An endogenous glucocorticoid-cytokine signaling circuit promotes CD8⁺T cell dysfunction in the tumor microenvironment

Cited by 2 publications

References 66 publications

Control of T Cell Metabolism by Cytokines and Hormones

Control of T Cell Metabolism by Cytokines and Hormones

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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An endogenous glucocorticoid-cytokine signaling circuit promotes CD8+T cell dysfunction in the tumor microenvironment

Cited by 2 publications

References 66 publications

Control of T Cell Metabolism by Cytokines and Hormones

Control of T Cell Metabolism by Cytokines and Hormones

Distinct CD8+T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome

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An endogenous glucocorticoid-cytokine signaling circuit promotes CD8⁺T cell dysfunction in the tumor microenvironment

Distinct CD8⁺T Cell Programming in the Tumor Microenvironment Contributes to Sex Bias in Bladder Cancer Outcome