Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer

Awasthi, Shivanshu; Berglund, Anders; Abraham-Miranda, Julieta; Rounbehler, Robert J.; Kensler, Kevin H.; Serna, Amparo; Vidal, Adriana C.; You, Sungyong; Freeman, Michael R.; Davicioni, Elai; Liu, Yang; Karnes, R. Jeffrey; Klein, Eric A.; Den, Robert B.; Trock, Bruce J.; Campbell, Joshua D.; Einstein, David J.; Gupta, Raavi; Balk, Steven P.; Lal, Priti; Park, Jong Y.; Cleveland, John L.; Rebbeck, Timothy R.; Freedland, Stephen J.; Yamoah, Kosj

doi:10.1158/1078-0432.ccr-20-2925

Cited by 54 publications

(69 citation statements)

References 37 publications

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“…High numbers of CD8 + tumor infiltrating lymphocytes (TILs) positively correlated with PD-L1 expression. Interestingly, PD-L1 expression was more frequent in tumors from Black patients, consistent with data suggesting uniquely immunogenic phenotypes in this population (17-20).…”

Section: Introductionsupporting

confidence: 86%

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Calagua

Ficial

Jansen

et al. 2021

Preprint

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PurposeA subset of primary prostate cancer (PCa) expresses programmed death-ligand 1 (PD-L1), but whether they have unique tumor immune microenvironment (TIME) or genomic features is unclear.Experimental DesignWe selected PD-L1-positive high-grade and/or high-risk primary PCa, characterized tumor-infiltrating lymphocytes (TILS) with multiplex immunofluorescence, and identified genomic alterations in immunogenic and non-immunogenic tumor foci.ResultsOne-quarter of aggressive localized PCa cases (29/115) had tumor PD-L1 expression >5%. This correlated with increased density of CD8+ T cells, a large fraction co-expressing PD-1, versus absent PD-1 expression on sparse CD8 T cells in unselected cases. Most CD8+PD-1+ cells did not express terminal exhaustion markers (TIM-3 or LAG-3), while a subset expressed TCF1. Consistent with these CD8+PD-1+TCF1+ cells being progenitors, they were found in antigen-presenting-cell niches in close proximity to MHC II+ cells. CD8 T cell density in immunogenic PCa and renal cell carcinoma (RCC) was nearly identical. Shallow RB1 and BRCA2 losses, and deep deletions of CHD1, were prevalent; the latter being strongly associated with a dendritic cell gene set in TCGA. Tumor mutation burden was variable; neither high microsatellite instability nor CDK12 alterations were present.ConclusionsA subset of localized PCa is immunogenic, manifested by PD-L1 expression and CD8+ T cell content comparable to RCC. The CD8+ T cells include effector cells and exhausted progenitor cells, which may be expanded by ICIs. Genomic losses of RB1, BRCA2, and CHD1 may be drivers of this phenotype. These findings indicate that immunotherapies may be effective in biomarker-selected subpopulations of localized PCa patients.Statement of Translational RelevanceProstate cancer (PCa) is generally considered poorly immunogenic, with low expression of programmed death-ligand 1 (PD-L1) and low density of tumor-infiltrating immune cells. Accordingly, response rates to PD(L)-1 inhibition in unselected patients with advanced prostate cancer have been low. Here, we find that a substantial subset of aggressive primary PCa exhibits tumor PD-L1 expression and contains a high density of tumor-infiltrating lymphocytes. These lymphocytes contain sub-populations of exhausted progenitor CD8+ T cells and differentiated effector T cells, the hallmarks of ongoing anti-tumor immune response and a prerequisite for response to checkpoint inhibition. Furthermore, we identify genomic alterations that may be contributing to immunogenicity in these cases. These findings point to immune responses elicited in a subset of primary PCa, supporting the development of immune checkpoint blockade clinical trials in early-stage disease, such as biochemically recurrent PCa, that are driven by genomic features of the tumor or the immune microenvironment.

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Section: Introductionsupporting

confidence: 86%

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Calagua

Ficial

Jansen

et al. 2021

Preprint

Self Cite

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“…To summarize, our results provide a rationale for moving treatments targeting androgen metabolizing enzymes and AR transcriptional activity earlier in the disease continuum, even in the treatment naïve setting for AA men with PrCa. In the era of personalized and precision medicine, our study along with other ongoing efforts [86][87][88][89][90] , emphasize the need to include underrepresented racial groups to understand and develop better prognostic and diagnostic indicators in the PrCa disease continuum.…”

Section: Discussionmentioning

confidence: 99%

Racial differences in androgen metabolism and receptor signaling in prostate cancer

Ramakrishnan

Attwood

et al. 2021

Preprint

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Dihydrotestosterone (DHT) and testosterone (T) mediated androgen receptor (AR) nuclear translocation initiates transcription of AR target genes that are pivotal for prostate cancer (PrCa) development and progression. Here we provide data indicating that in contrast to European American (EA) men, African American (AA) men with localized PrCa can exploit an alternative progesterone-androsterone-5α-androstanedione pathway for DHT biosynthesis. Enzymes that are involved in alternate pathways of DHT biosynthesis are elevated in PrCa tissues from AA men, compared to EA men, and also correlated with increased serum DHT levels. In addition, higher serum DHT levels also reflect increased RNA expression of AR target genes in PrCa tissues from AA men. Interestingly, serum T but not DHT levels are significantly lower in AA men compared to EA men with PrCa. Furthermore, serum progesterone and related intermediate metabolites levels that are produced in the alternate biosynthetic pathways are significantly lower in AA men with PrCa and associated with a shorter time to disease progression. These data highlight that androgen biosynthesis is altered in therapy naïve localized PrCa in AA men, and can potentially serve as prognostic indicators of disease progression. Significance Our work provides a rationale to examine potential pharmacological interventions that target androgen biosynthesis and AR signaling earlier in the disease continuum in AA men with PrCa. Additionally, our study lays the groundwork for developing serum measurements of intermediate androgen metabolites as PrCa prognostic biomarkers.

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“…The influx of pro-inflammatory markers including stromal derived BDNF activate signaling pathways such as PI3K/AKT via tropomyosin receptor kinase B (TrkB) phosphorylation that may explain the aggressive nature of PCa in AA men [ 18 ]. The tumors from AA patients have a higher density of pro-tumorigenic immune cells and inflammatory cytokines compared to EA patients [ 63 ]. The prostate tumors of AA men showed a unique signature of pro-inflammatory cytokines, interferon-alpha (IFNα), IFNγ, tumor necrosis factor-alpha (TNFα), and Interleukin 4 and Interleukin 13 signaling that was associated with metastases and poor prognosis [ 63 ].…”

Section: Race Tme and Tumor Sitementioning

confidence: 99%

“…The tumors from AA patients have a higher density of pro-tumorigenic immune cells and inflammatory cytokines compared to EA patients [ 63 ]. The prostate tumors of AA men showed a unique signature of pro-inflammatory cytokines, interferon-alpha (IFNα), IFNγ, tumor necrosis factor-alpha (TNFα), and Interleukin 4 and Interleukin 13 signaling that was associated with metastases and poor prognosis [ 63 ].…”

Section: Race Tme and Tumor Sitementioning

confidence: 99%

Race as a Contributor to Stromal Modulation of Tumor Progression

Kakarla

ChallaSivaKanaka

Hayward

et al. 2021

Cancers

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Stromal cells play crucial roles in tumor development and are increasingly attractive targets for therapy. There are considerable racial disparities in the incidence and progression of many tumors, reflecting both environmental exposure and genetic differences existing between races. Tumorigenesis and tumor progression are linked to both the propensity to suffer an initiating event and the host response to such an event once it occurs, contributing to incidence and outcomes. In this review, we focused on racial disparities in the tumor microenvironment (TME) of different cancers as potential modulators of growth, metastasis, and response to treatment. Several studies suggest that the TME in AA has a distinct tumor biology and may facilitate both early onset and aggressive tumor growth while inhibiting anti-tumorigenic properties. The TME of AA patients often exhibits an immunosuppressive microenvironment with a substantial enrichment of immune inflammatory pathways and genes. As a result, AA patients can potentially benefit more from treatment strategies that modulate the immune system. Focusing on TME components for diagnostic and therapeutic purposes to address racial disparities is a promising area of investigation. Future basic and clinical research studies on personalized cancer diagnosis and treatment should acknowledge the significance of TME in racial disparities.

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Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer

Cited by 54 publications

References 37 publications

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

A Subset of Localized Prostate Cancer Displays an Immunogenic Phenotype Associated with Losses of Key Tumor Suppressor Genes

Racial differences in androgen metabolism and receptor signaling in prostate cancer

Race as a Contributor to Stromal Modulation of Tumor Progression

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