The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression

Su, Wenjing; Han, Hyun Ho; Wang, Yan; Zhang, Boyu; Zhou, Bing; Cheng, Yuanming; Rumandla, Alekya; Gurrapu, Sreeharsha; Chakraborty, Goutam; Su, Jie; Yang, Guangli; Liang, Xin; Wang, Guocan; Rosen, Neal; Scher, Howard I.; Ouerfelli, Ouathek; Giancotti, Filippo G.

doi:10.1016/j.ccell.2019.06.009

Cited by 158 publications

(128 citation statements)

References 65 publications

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“…S14). In concordance with our data, it was recently shown that inhibition of polycomb repressor complex-1 in double-negative PCa models resulted in increased T-cell tumor infiltration, decreased immune suppressive cells and provided superior therapeutic benefit when combined with CPI(27).Identifying mechanisms driving resistance towards checkpoint immunotherapy in PCa patients remains a critical requirement. While progress has been made describing molecular events that increase response, including patients with DNA damage repair pathway defects(28,29), biallelic loss of CDK12 (30), recycling of PD-L1 in patients lacking a common mutation in SPOP(31), and inhibition of IL-23(32), the majority of patients treated with CPI remain unresponsive.…”

supporting

confidence: 89%

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Sheahan

Morel

Burkhart

et al. 2019

Preprint

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Prostate cancers are considered immunologically ‘cold’ tumors given the very few patients who respond to checkpoint inhibitor therapy (CPI). Recently, enrichment of interferon (IFN) response genes predicts a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is over-expressed in prostate cancer and is known to negatively regulate IFN response genes. Here, we demonstrate that inhibition of EZH2 catalytic activity in prostate cancer models derepresses expression of double-strand RNA (dsRNA), associated with upregulation of genes involved in antigen presentation, Th-1 chemokine signaling, and interferon (IFN) response, including PD-L1. Similarly, application of a novel EZH2 derived gene signature to human prostate sample analysis indicated an inverse correlation between tumor EZH2 activity/expression with T-cell inflamed and IFN gene signatures and PD-L1 expression. EZH2 inhibition combined with PD-1 CPI significantly enhances antitumor response that is dependent on up-regulation of tumor PD-L1 expression. Further, combination therapy significantly increases intratumoral trafficking of activated CD8+ T-cells and M1 tumor associated macrophages (TAMs) with concurrent loss of M2 TAMs. Our study identifies EZH2 as a potent inhibitor of antitumor immunity and responsiveness to CPI. This data suggests EZH2 inhibition as a novel therapeutic direction to enhance prostate cancer response to PD-1 CPI.

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supporting

confidence: 89%

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Sheahan

Morel

Burkhart

et al. 2019

Preprint

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“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in PCa is depicted in Table 3 [108,[141][142][143][144][145][146][147][148][149][150][151][152]. Some studies have focused on epigenetic regulation of response to IFN, where both methylation and acetylation can be involved, as demonstrated by Dunn and collaborators [141].…”

Section: Role Of Immunoepigenetics?mentioning

confidence: 99%

“…Like for CTAs, decitabine also restored/induced the expression of the chemokine CXCL14, which functions as a chemoattractant for dendritic cells [145]. On the other hand, Su and coworkers [151] have focused on CCL2. In their work, they uncovered that the polycomb repressor complex 1 (PRC1) in androgen-receptor and neuroendocrine double-negative PCa is responsible for producing metastases, by regulating CCL2 expression.…”

Section: Role Of Immunoepigenetics?mentioning

confidence: 99%

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Lobo

Jerónimo

Henrique

2020

IJMS

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In the last years, we have witnessed remarkable advances in targeted therapies for cancer patients. There is a growing effort to either replace or reduce the dose of unspecific, systemic (chemo)therapies, given the associated short- and long-term side effects, by introducing more specific targeted therapies as single or combination agents. Due to the well-known implications of the immune system and epigenetic landscape in modulating cancer development, both have been explored as potential targets in several malignancies, including those affecting the genitourinary tract. As the immune system function is also epigenetically regulated, there is rationale for combining both strategies. However, this is still rather underexplored, namely in urological tumors. We aim to briefly review the use of immune therapies in prostate, kidney, bladder, and testicular cancer, and further describe studies providing supporting evidence on their combination with epigenetic-based therapies.

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“…This trend also held true for another two chemokines CCL3 and CCL4 (figure 4C, p<0.01). Tumor-derived CCL2 and CCL5 are significant indicators of early relapse and the infiltration of tumor-associated macrophages (TAMs), which contribute to cancer cell proliferation, the inflammatory microenvironment, immune evasion and angiogenesis 21–23. The proportion of TAM infiltration deduced by CIBERSORT was significantly higher in the MSI-H1 subgroup than in the MSI-H2 subgroup (online supplementary figure S3, p = 0.007, Wilcoxon test).…”

Section: Resultsmentioning

confidence: 99%

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival

et al. 2020

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BackgroundMicrosatellite instability-high (MSI-H) tumour patients generally have a better prognosis than microsatellite-stable (MSS) ones due to the large number of non-synonymous mutations. However, an increasing number of studies have revealed that less than half of MSI-H patients gain survival benefits or symptom alleviation from immune checkpoint-blockade treatment. Thus, an in-depth inspection of heterogeneous MSI-H tumours is urgently required.MethodsHere, we used non-negative matrix factorisation (non-NMF)-based consensus clustering to define stomach adenocarcinoma (STAD) MSI-H subtypes in samples from The Cancer Genome Atlas and an Asian cohort, GSE62254.ResultsMSI-H STAD samples are basically clustered into two subgroups (MSI-H1 and MSI-H2). Further examination of the immune landscape showed that immune suppression factors were enriched in the MSI-H1 subgroup, which may be associated with the poor prognosis in this subgroup.ConclusionsOur results illustrate the genetic heterogeneity within MSI-H STADs, with important implications for cancer patient risk stratification, prognosis and treatment.

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The Polycomb Repressor Complex 1 Drives Double-Negative Prostate Cancer Metastasis by Coordinating Stemness and Immune Suppression

Cited by 158 publications

References 65 publications

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate Cancer

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

Heterogeneity of MSI-H gastric cancer identifies a subtype with worse survival

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