Detailed Molecular and Immune Marker Profiling of Archival Prostate Cancer Samples Reveals an Inverse Association between TMPRSS2:ERG Fusion Status and Immune Cell Infiltration

Rao, S. Madhusudana; Alham, Nasullah Khalid; Upton, Elysia; McIntyre, Stacey; Bryant, Richard J.; Cerundolo, Lucia; Bowes, Emma; Jones, Stephanie; Browne, Molly; Mills, Ian G.; Lamb, Alastair; Tomlinson, Ian; Wedge, David C.; Browning, Lisa; Sirinukunwattana, Korsuk; Palles, Claire; Hamdy, Freddie C.; Rittscher, Jens; Verrill, Clare

doi:10.1016/j.jmoldx.2020.02.012

Cited by 6 publications

(6 citation statements)

References 62 publications

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“…However, there are mixed findings regarding the presence of inflammation by the ERG-defined subtype. An inverse association between TMPRSS2-ERG fusion and TILs was identified by integrating an image analysis with RNA sequencing in 27 archival radical prostatectomy cases [76]. In contrast, Burdova et al found that CD204+ macrophages and CD3+ T-lymphocytes may infiltrate the tumor region more intensely in TMPRSS2-ERG fusion-positive cases, compared to fusion-negative cases [77], in line with findings from Kaur and colleagues, showing increased T-cell density in ERGpositive tumors [78].…”

Section: Heterogeneity Among Immune Phenotypessupporting

confidence: 52%

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention

Huang

LaBonte

Craig

et al. 2022

Cancers

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Prostate cancer is a major cause of disease for men globally. Inflammation, an established hallmark of cancer, is frequently observed in the prostate, though its contribution to prostate cancer risks and outcomes is not fully understood. Prostate cancer is biologically and clinically heterogeneous, and there is now evidence that inflammation and immunological characteristics vary by the genomic and mutational landscape of the tumor. Moreover, it is now recognized that risk factor profiles vary between tumor subgroups, as defined by histopathological and molecular features. Here, we provide a review centered around the relationship between inflammation and prostate cancer, with a consideration of molecular tumor features and a particular focus on the advanced and lethal stages of disease. We summarize findings from epidemiological studies of the etiology and role of inflammation in prostate cancer. We discuss the pathology of prostate inflammation, and consider approaches for assessing the tumor immune microenvironment in epidemiological studies. We review emerging clinical therapies targeting immune biology within the context of prostate cancer. Finally, we consider potentially modifiable risk factors and corresponding lifestyle interventions that may affect prostate inflammation, impacting outcomes. These emerging insights will provide some hints for the development of treatment and prevention strategies for advanced and lethal prostate cancer.

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Section: Heterogeneity Among Immune Phenotypessupporting

confidence: 52%

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention

Huang

LaBonte

Craig

et al. 2022

Cancers

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“…Whether the presence/type of immune cells serves as the driving force for fusion‐driven PCa or whether the fusion‐state is responsible for the influx of immune cells in the prostate tumor microenvironment warrants further investigation, which is beyond the scope of the present study. It is intriguing that previously published studies investigating the association between immune cell infiltration and presence of TMPRSS2‐ERG fusion in clinical samples have reported either a positive relationship 55 between increased prostate inflammation and TMPRSS2‐ERG fusion or inverse relationship 56 between the two. Nevertheless, the strong presence of immune cells in the fusion‐driven PCa is one remarkable and novel observation from the present study that cannot be overlooked; it has the potential to serve as a potential indicator of fusion‐driven PCa and could very well serve as a target for future therapies specific against fusion‐driven PCa.…”

Section: Discussionmentioning

confidence: 99%

Characterization of stage‐specific tumor progression in TMPRSS2‐ERG (fusion)‐driven and non‐fusion‐driven prostate cancer in GEM models

Raina

Kant

Prasad

et al. 2022

Molecular Carcinogenesis

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In the present study, we performed a comparative stage-specific pathological and molecular marker evaluation of TMPRSS2-ERG fusion and PTEN loss-driven (TMPRSS2-ERG. Pten flox/flox ) versus non-fusion-driven prostate tumorigenesis (Hi-Myc) in mice. Anterior, ventral, and dorsolateral prostates were collected from mice at different ages (or time points post-Cre induction). Results indicated that growth and progression of prostatic intraepithelial lesions to adenocarcinoma stages occurred in both mice models albeit at different rates. In the TMPRSS2-ERG. Pten flox/ flox mice, the initiation of tumorigenesis was slow, but subsequent progression through different stages became increasingly faster. Adenocarcinoma stage was reached early on; however, no high-grade undifferentiated tumors were observed.Conversely, in the Hi-Myc +/− mice, tumorigenesis initiation was rapid; however, progression through different stages was relatively slower and it took a while to reach the more aggressive phenotype stage. Nevertheless, at the advanced stages in the Hi-Myc +/− mice, high-grade undifferentiated tumors were observed compared to the later stage tumors observed in the fusion-driven TMPRSS2-ERG. Pten flox/flox mice. These results were corroborated by the stage specific-pattern in the molecular expression of proliferation markers (PCNA and c-Myc); androgen receptor (AR); fusion-resultant overexpression of ERG; Prostein (SLC45-A3); and angiogenesis

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“…This finding suggests that the Tmprss2-Erg fusion promotes recruitment of regulatory T cells to the tumor site [50]. Recent studies have shown an association between low levels of TILs comparing TMPRSS2-ERG fusions producing chimeric transcripts in the coding in the fusion-positive cases results in suppression of immune response by alteration of cytokine production [51,52].…”

Section: Phosphatase and Tensin Homologue (Pten)mentioning

confidence: 97%

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Melo

Vidotto

Chaves

et al. 2021

IJMS

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Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.

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Detailed Molecular and Immune Marker Profiling of Archival Prostate Cancer Samples Reveals an Inverse Association between TMPRSS2:ERG Fusion Status and Immune Cell Infiltration

Cited by 6 publications

References 62 publications

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention

Inflammation and Prostate Cancer: A Multidisciplinary Approach to Identifying Opportunities for Treatment and Prevention

Characterization of stage‐specific tumor progression in TMPRSS2‐ERG (fusion)‐driven and non‐fusion‐driven prostate cancer in GEM models

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

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