Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

Vellano, Christopher P.; White, Michael G.; Andrews, Miles C.; Chelvanambi, Manoj; Witt, Russell G.; Daniele, Joseph R.; Titus, Mark A.; McQuade, Jennifer L.; Conforti, Fabio; Burton, Elizabeth M.; Lastrapes, Matthew; Ologun, Gabriel O; Cogdill, Alexandria P.; Morad, Golnaz; Prieto, Peter A.; Lazar, Alexander J.; Chu, Yanshuo; Han, Guangchun; Khan, M.A. Wadud; Helmink, Beth A.; Davies, Michael A.; Amaria, Rodabe N.; Kovacs, Jeffery; Woodman, Scott E.; Patel, Sapna; Hwu, Patrick; Peoples, Michael; Lee, Jeffrey E.; Cooper, Zachary A.; Zhu, Haifeng; Gao, Guang R.; Banerjee, Hiya; Lau, Mike; Gershenwald, Jeffrey E.; Lucci, Anthony; Keung, Emily Z.; Ross, Merrick I.; Pala, Laura; Pagan, Eleonora; Segura, Rossana Lazcano; Liu, Qian; Borthwick, Mikayla S; Lau, Eric; Yates, Melinda S.; Westin, Shannon N.; Wani, Khalida; Tetzlaff, Michael T.; Haydu, Lauren E.; Mahendra, Mikhila; Ma, Xiao-Yan; Logothetis, Christopher J.; Kulstad, Zachary; Johnson, Sarah; Hudgens, Courtney W.; Feng, Ningping; Federico, Lorenzo; Long, Georgina V.; Futreal, Andrew; Arur, Swathi; Tawbi, Hussein A.; Moran, Amy E.; Wang, Linghua; Heffernan, Timothy; Marszalek, Joseph R.; Wargo, Jennifer A.

doi:10.1038/s41586-022-04833-8

Cited by 76 publications

(55 citation statements)

References 58 publications

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“…In our analysis, the gender group showed a bias phenomenon regarding CD8 + Runx3 + , CD8 + CTSW + cytotoxic, and CD8 + exhaustion. Recently, a series of clinical and experimental studies reported that gender has a significant impact on the effectiveness of antitumor immunotherapy ( 65 – 67 ). In patients with colorectal cancer or melanoma, the androgen receptor (AR) mediated signaling pathways impaired the stem-cell like feature of CD8 + T cells, resulting in CD8 + T cell exhaustion in male tumor patients, whereas female patients with lower AR expression and androgen levels gained better antitumor immunity ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers

Liu

et al. 2022

Front. Immunol.

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BackgroundThe main objective of this study was to analyze the effects of KRAS/TP53 mutation status and tumor sideness on the immune microenvironment of colorectal cancer using integrated scRNA-seq data.MethodsA total of 78 scRNA-seq datasets, comprising 42 treatment-naive colorectal tumors, 13 tumor adjacent tissues and 23 normal mucosa tissues were included. Standardized Seurat procedures were applied to identify cellular components with canonical cell marks. The batch-effect was assessed and corrected using harmony algorithm. The scMetabolism algorithm was used for single-cell metabolic analysis. The results and clinical significance were further validated using immunofluorescent-staining and TCGA-COAD datasets. Immune-infiltration scores of bulk-RNA-seq data were estimated using ssGSEA. The presto-wilcoxauc algorithm was used to identify differentially enriched genes or pathways across different subgroups. Two-sided p-value less than 0.05 was considered statistically significant.ResultsWe refined the landscape of functional immune cell subtypes, especially T cells and myeloid cells, across normal mucosa, tumor adjacent and tumor tissue. The existence and function of two states of exhausted CD8+ T (Tex) subtypes in colorectal cancer, and FOLR2+ LYVE1+ macrophages indicating unfavorable prognosis in colorectal cancer were identified and validated. The diverse tumor mutation status reshaped the immune cell function and immune checkpoint ligands/receptors (ICLs/ICRs) expression pattern. Importantly, the KRAS/TP53 dual mutations significantly reduced the major energy metabolic functions in immune cells, and promoted the cell-to-cell communications towards immunosuppression in colorectal cancers. The results revealed LAG3, CD24-SIGLEC10 and HBEGF-CD9 pathways as potential therapeutic targets for dual mutant colorectal cancers.ConclusionsWe revealed that the immune microenvironment underwent a gradual remodeling with an enrichment of immunosuppressive myeloid cells from normal mucosa to tumor regions in colorectal cancers. Moreover, we revealed the metabolic heterogeneity of tumor-infiltrating immune cells and suggested that the KRAS/TP53 dual mutation may impair antitumor immunity by reducing T and myeloid cell energy metabolism and reshaping cellular interactions toward immunosuppression.

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Section: Discussionmentioning

confidence: 99%

Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers

Liu

et al. 2022

Front. Immunol.

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“…Genetic or pharmacological suppression of AR activity in melanoma cells hinders their proliferation [ 10 ]. Very recently, Vellano et al demonstrated that AR blockage promoted a better response to BRAF/MEK-targeted therapy in melanoma patients, thus improving recurrence-free survival [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

Orlandi

Tomi

Campagnari

et al. 2022

CIMB

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Polymorphisms in the ribonuclease L (RNASEL) coding gene and hsa-miR-146a-5p (miR-146a) have been associated with melanoma in a sex-specific manner. We hypothesized that RNASEL and miR-146a expression could be influenced by sex hormones playing a role in the female advantages observed in melanoma incidence and survival. Thus, we explored the effects of testosterone and 17β-estradiol on RNASEL and miR-146a expression in LM-20 and A375 melanoma cell lines. Direct targeting of miR-146a to the 3’ untranslated region (3′UTR) of RNASEL was examined using a luciferase reporter system. Our results indicate that RNASEL is a direct target of miR-146a in both melanoma cell lines. Trough qPCR and western blot analyses, we explored the effect of miR-146a mimic transfection in the presence of each hormone either on RNASEL mRNA level or on protein expression of RNase-L, the enzyme codified by RNASEL gene. In the presence of testosterone or 17β-estradiol, miR-146a overexpression did not influence RNASEL transcript level in LM-20 cell line, but it slightly induced RNASEL mRNA level in A375 cells. Remarkably, miR-146a overexpression was able to repress the protein level of RNase-L in both LM-20 and A375 cells in the presence of each hormone, as well as to elicit high expression levels of the activated form of the extracellular signal-regulated kinases (ERK)1/2, hence confirming the pro-tumorigenic role of miR-146a overexpression in melanoma. Thereafter, we assessed if the administration of each hormone could affect the endogenous expression of RNASEL and miR-146a genes in LM-20 and A375 cell lines. Testosterone exerted no significant effect on RNASEL gene expression in both cell lines, while 17β-estradiol enhanced RNASEL transcript level at least in LM-20 melanoma cells. Conversely, miR-146a transcript augmented only in the presence of testosterone in either melanoma cell line. Importantly, each hormone acted quite the opposite regarding the RNase-L protein expression, i.e., testosterone significantly decreased RNase-L expression, whereas 17β-estradiol increased it. Overall, the data show that, in melanoma cells treated with 17β-estradiol, RNase-L expression increased likely by transcriptional induction of its gene. Testosterone, instead, decreased RNase-L expression in melanoma cell lines with a post-transcriptional mechanism in which miR-146a could play a role. In conclusion, the pro-tumor activity of androgen hormone in melanoma cells could be exacerbated by both miR-146a increase and RNase-L downregulation. These events may contribute to the worse outcome in male melanoma patients.

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“…Sex hormone signaling pathways are likely to affect cancer susceptibility and prognosis through multiple intrinsic and extrinsic mechanisms. The latest study by Vellano et al revealed that the expression of androgen receptors was significantly increased in male patients during BRAF/MEK targeted therapy and was associated with therapeutic resistance [ 81 ]. Yang et al identify that AR signaling accelerates the transition from stem cell-like CD8 + T cells to terminally exhausted CD8 + T cells in males, leading to sex-biased anti-tumor immunity.…”

Section: Sex Disparities In Sex Hormone and Hormone Receptor-mediated...mentioning

confidence: 99%

Advances in sex disparities for cancer immunotherapy: unveiling the dilemma of Yin and Yang

Yao

Chen

et al. 2022

Biol Sex Differ

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A wide sex disparity has been demonstrated in cancer incidence, tumor aggressiveness, prognosis, and treatment response of different types of cancer. The sex specificity of cancer appears to be a relevant issue in managing the disease, and studies investigating the role of sex and gender are becoming extremely urgent. Immunotherapy plays a leading role in cancer treatment, offering a new perspective on advanced malignancies. Gender has not been considered in standard cancer treatment, suggesting increasing the recognition of sex differences in cancer research and clinical management. This paper provides an overview of sex and gender disparities in cancer immunotherapy efficacy, anti-cancer immune response, predictive biomarkers, and so on. We focus on the molecular differences between male and female patients across a broad range of cancer types to arouse the attention and practice of clinicians and researchers in a sex perspective of new cancer treatment strategies.

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Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy

Cited by 76 publications

References 58 publications

Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers

Integrated single-cell RNA-seq analysis identifies immune heterogeneity associated with KRAS/TP53 mutation status and tumor-sideness in colorectal cancers

Human Melanoma Cells Differentially Express RNASEL/RNase-L and miR-146a-5p under Sex Hormonal Stimulation

Advances in sex disparities for cancer immunotherapy: unveiling the dilemma of Yin and Yang

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