Association of tumor-infiltrating T-cell density with molecular subtype, racial ancestry and clinical outcomes in prostate cancer.
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ABSTRACT:
SUBMITTER: Kaur HB
PROVIDER: S-EPMC6168349 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Association of tumor-infiltrating T-cell density with molecular subtype, racial ancestry and clinical outcomes in prostate cancer.
Kaur Harsimar B HB Guedes Liana B LB Lu Jiayun J Maldonado Laneisha L Reitz Logan L Barber John R JR De Marzo Angelo M AM Tosoian Jeffrey J JJ Tomlins Scott A SA Schaeffer Edward M EM Joshu Corinne E CE Sfanos Karen S KS Lotan Tamara L TL
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 20180530 10
The inflammatory microenvironment plays an important role in the pathogenesis and progression of tumors and may be associated with somatic genomic alterations. We examined the association of tumor-infiltrating T-cell density with clinical-pathologic variables, tumor molecular subtype, and oncologic outcomes in surgically treated primary prostate cancer occurring in patients of European-American or African-American ancestry. We evaluated 312 primary prostate tumors, enriched for patients with Afr ...[more]
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Project description:BackgroundB7 homolog 3 (B7-H3) is an immunomodulatory molecule that is highly expressed in prostate cancer (PCa) and belongs to the B7 superfamily, which includes PD-L1. Immunotherapies (antibodies, antibody-drug conjugates, and chimeric antigen receptor T cells) targeting B7-H3 are currently in clinical trials; therefore, elucidating the molecular and immune microenvironment correlates of B7-H3 expression may help to guide trial design and interpretation. The authors tested the interconnected hypotheses that B7-H3 expression is associated with genetic racial ancestry, immune cell composition, and androgen receptor signaling in PCa.MethodsAn automated, clinical-grade immunohistochemistry assay was developed by to digitally quantify B7-H3 protein expression across 2 racially diverse cohorts of primary PCa (1 with previously reported transcriptomic data) and pretreatment and posttreatment PCa tissues from a trial of intensive neoadjuvant hormonal therapy.ResultsB7-H3 protein expression was significantly lower in self-identified Black patients and was inversely correlated with the percentage African ancestry. This association with race was independent of the significant association of B7-H3 protein expression with ERG/ETS and PTEN status. B7-H3 messenger RNA expression, but not B7-H3 protein expression, was significantly correlated with regulatory (FOXP3-positive) T-cell density. Finally, androgen receptor activity scores were significantly correlated with B7-H3 messenger RNA expression, and neoadjuvant intensive hormonal therapy was associated with a significant decrease in B7-H3 protein expression.ConclusionsThe current data underscore the importance of studying racially and molecularly diverse PCa cohorts in the immunotherapy era. This study is among the first to use genetic ancestry markers to add to the emerging evidence that PCa in men of African ancestry may have a distinct biology associated with B7-H3 expression.Lay summaryB7-H3 is an immunomodulatory molecule that is highly expressed in prostate cancer and is under investigation in clinical trials. The authors determined that B7-H3 protein expression is inversely correlated with an individual's proportion of African ancestry. The results demonstrate that B7-H3 messenger RNA expression is correlated with the density of tumor T-regulatory cells. Finally, in the first paired analysis of B7-H3 protein expression before and after neoadjuvant intensive hormone therapy, the authors determined that hormone therapy is associated with a decrease in B7-H3 protein levels, suggesting that androgen signaling may positively regulate B7-H3 expression. These results may help to guide the design of future clinical trials and to develop biomarkers of response in such trials.
| S-EPMC9133095 | biostudies-literature
Project description:Tumors commonly are infiltrated by leukocytes, or tumor infiltrating leukocytes (TILs). It remains unclear, however, if the density and type of individual TILs has a direct or simply correlative role in promoting poor prognosis in breast cancer patients. Breast cancer in Kenyan women is aggressive with presentation at a young age, with advanced grade (grade III), large tumor size (>2.0 cm), and poor prognosis. We previously observed that the tumors were predominantly estrogen receptor positive (ER+) but also included both a high percentage of triple negative tumors and also increased immune cell infiltration within the tumors. We used breast tumor tissues from each patient to make tissue microarrays that were then stained for leukocyte and myeloid markers including CD4, CD8, CD20, CD25, CD68, and CD163 using immunohistochemical techniques. The immune cell infiltration into the cancer tissue included increased numbers of macrophages (CD68+), helper T cells (CD4+), and CD25+ lymphocytes compared to benign tissue.This study characterized the grade, molecular subtypes, and proliferation index of these tumors and determined if TIL density was enriched across any of these factors. We analyzed 49 malignant patient tissue samples for this study. The patient population had a mean age of 51.9 years. The tumors analyzed were heterogeneous by grade: grade I (6%), grade II (47%), and grade III (39%). Most patients presented with large tumors (>2.0 cm) (69%). We classified the tumors into molecular subtypes based on clinical marker expression. Based on this analysis, the molecular subtype distribution was heterogeneous with luminal B (41%), basal/triple negative (TN) (37%), luminal A (14%) and HER2 (8%) breast cancer subtypes. While the basal/TN subtype had a much higher proliferative index (Ki-67+) than did the other molecular subtypes, we did not see a significant correlation between TIL density and either subtype or tumor grade. Therefore, TIL density is independent of molecular subtype and grade.This study identified a Kenyan patient cohort that develops large, high-grade tumors primarily of the luminal B and basal molecular subtypes. After analyzing the TILs within these tumors, we found that immune cell infiltration of these tumors correlated with increased proliferation but not grade or molecular subtype. Future research is required to determine if the aberrant recruitment of TILs to tumors contributes to cancer progression and response to cancer treatments.
| S-EPMC5543450 | biostudies-other
Project description:Racial disparities in survival among African American (AA) women in the United States have been well documented. Breast cancer mortality rates among AA women is higher in Memphis, Tennessee as compared to 49 of the largest US cities. In this study, we investigated the extent to which racial/ethnic disparities in survival outcomes among Memphis women are attributed to differences in breast tumor subtype and treatment outcomes. A total of 3527 patients diagnosed with stage I-IV breast cancer between January 2002 and April 2015 at Methodist Health hospitals and West Cancer Center in Memphis, TN were included in the analysis. Kaplan-Meier survival curves were generated and Cox proportional hazards regression were used to compare survival outcomes among 1342 (38.0%) AA and 2185 (62.0%) non-Hispanic White breast cancer patients by race and breast tumor subtype. Over a mean follow-up time of 29.9 months, AA women displayed increased mortality risk [adjusted hazard ratio (HR), 1.65; 95% confidence interval (CI), 1.35-2.03] and were more likely to be diagnosed at advanced stages of disease. AA women with triple-negative breast cancer (TNBC) had the highest death rate at 26.7% compared to non-Hispanic White women at 16.5%. AA women with TNBC and luminal B/HER2- breast tumors had the highest risk of mortality. Regardless of race, patients who did not have surgery had over five times higher risk of dying compared to those who had surgery. These findings provide additional evidence of the breast cancer disparity gap between AA and non-Hispanic White women and highlight the need for targeted interventions and policies to eliminate breast cancer disparities in AA populations, particularly in Memphis, TN.
| S-EPMC5504313 | biostudies-other
Project description:BackgroundThere are known disparities in incidence and outcomes of colorectal cancer (CRC) by race and ethnicity. Some of these disparities may be mediated by molecular changes in tumors that occur at different rates across populations. Genetic ancestry is a measure complementary to race and ethnicity that can overcome missing data issues and better capture genetic similarity in admixed populations. We aimed to identify somatic mutations and tumor gene expression differences associated with both genetic ancestry and imputed race and ethnicity.MethodsSequencing was performed with the Tempus xT NGS 648-gene panel and whole exome capture RNA-Seq for 8454 primarily late-stage CRC patients. Genetic ancestry proportions for five continental groups-Africa (AFR), American indigenous (AMR), East Asia (EAS), Europe (EUR), and South Asia (SAS)-were estimated using ancestry informative markers. To address data gaps, race and ethnicity categories were imputed, resulting in assignments for 952 Hispanic/Latino, 420 non-Hispanic (NH) Asian, 1061 NH Black, and 5763 NH White individuals. We assessed association of genetic ancestry proportions and imputed race and ethnicity categories with somatic mutations in relevant CRC genes and in 2608 expression profiles, as well as 1957 consensus molecular subtypes (CMS).ResultsIncreased AFR ancestry was associated with higher odds of somatic mutations in APC, KRAS, and PIK3CA and lower odds of BRAF mutations. Additionally, increased EAS ancestry was associated with lower odds of mutations in KRAS, EUR with higher odds in BRAF, and the Hispanic/Latino category with lower odds in BRAF. Greater AFR ancestry and the NH Black category were associated with higher rates of CMS3, while a higher proportion of Hispanic/Latino patients exhibited indeterminate CMS classifications.ConclusionsMolecular differences in CRC tumor mutation frequencies and gene expression that may underlie observed differences by race and ethnicity were identified. The association of AFR ancestry with increased KRAS mutations aligns with higher CMS3 subtype rates in NH Black patients. The increase of indeterminate CMS in Hispanic/Latino patients suggests that subtype classification methods could benefit from enhanced patient diversity.
| S-EPMC11321170 | biostudies-literature
Project description:Disparities in cancer incidence and outcome are common among the racial and ethnical minorities in the United States and are of significant social and clinical concern. Prostate cancer is the most commonly diagnosed non-cutaneous malignancy in American men and exhibits substantial racial disparities with African American men bearing the highest burden in terms of incidence and mortality. A multitude of factors, including socioeconomic, behavioral, and access to healthcare, have been implicated as the underlying causes of such disparities. More recent data also suggest that there are inherent molecular and biological differences in prostate tumors of patients having distinct racial backgrounds. Tumor microenvironment has tremendous impact on the course of cancer progression and clinical outcome and may also contribute to the racial disparities observed in prostate cancer. Therefore, a better understanding of critical differences in the tumor microenvironment components may provide newer directions to study the biological causes of prostate cancer health disparities and may identify novel therapeutic targets. This review discusses the findings related to the tumor microenvironment differences between African American and Caucasian American prostate cancer patients and makes suggestion regarding their potential significance in prostate cancer disparities.
| S-EPMC9910060 | biostudies-literature
Project description:BACKGROUNDMolecular characterization of prostate cancer (PCa) has revealed distinct subclasses based on underlying genomic alterations occurring early in the natural history of the disease. However, how these early alterations influence subsequent molecular events and the course of the disease over its long natural history remains unclear.METHODSWe explored the molecular and clinical progression of different genomic subtypes of PCa using distinct tumor lineage models based on human genomic and transcriptomic data. We developed transcriptional classifiers, and defined "early" and "late" categories of molecular subclasses from 8,158 PCa patients. Molecular subclasses were correlated with clinical outcomes and pathologic characteristics using Kaplan-Meier and logistic regression analyses.RESULTSWe identified PTEN and CHD1 alterations as subtype-specific late progression events specifically in ERG-overexpressing (ERG+) and SPOP-mutant tumors, respectively, and 2 distinct progression models consisting of ERG/PTEN (normal to ERG+ to PTEN-deleted) and SPOP/CHD1 (normal to SPOP-mutated to CHD1-deleted) with shared early tumorigenesis but distinct pathways toward progression. We found that within ERG+ and SPOP-mutant subtypes, late events were associated with worse prognosis. Importantly, the clinical and pathologic features associated with distinct late events at radical prostatectomy were strikingly different; PTEN deletions were associated with increased locoregional stage, while CHD1 deletions were only associated with increased grade, despite equivalent metastatic potential.CONCLUSIONThese findings suggest a paradigm in which specific subtypes of PCa follow distinct pathways of progression, at both the molecular and clinical levels. Therefore, the interpretation of common clinical parameters such as locoregional tumor stage may be influenced by the underlying tumor lineage, and potentially influence management decisions.FUNDINGProstate Cancer Foundation, National Cancer Institute, Urology Care Foundation, Damon Runyon Cancer Research Foundation, US Department of Defense, and the AIRC Foundation.
| S-EPMC8121518 | biostudies-literature
Project description:Prostate cancer (PCa) remains the most common cancer in American men. African-American (AA) men continue to have higher PCa prevalence and mortality rates compared to men in other populations. In addition to socioeconomic factors and lifestyle differences, molecular alterations contribute to this discrepancy. We summarize molecular genetics research results interrelated with the biology of PCa racial disparity. Androgen and androgen receptor (AR) pathways have long been associated with prostate growth. Racial differences have also been found among variants of genes of the enzymes involved in androgen biosynthesis and metabolism. Growth factors and their receptors are a potential cause of the disparity in PCa. Recent molecular and biotechnological approaches in the field of proteomics and genomics will greatly aid the advancement of translational research on racial disparity in PCa, which may help, in finding new prognostic markers and novel therapeutic approaches for the treatment of PCa in AA.
| S-EPMC5550772 | biostudies-literature
Project description:UnlabelledProstate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG(+), m-ETS(+), m-SPINK1(+), or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG(+) was more common in CA than AA men (47% vs 22%, p<0.001). AA men were more likely to be m-SPINK1(+) (13% vs 7%; p=0.069) and triple-negative (50% vs 37%; p=0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling.Patient summaryThis study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships.
| S-EPMC4826623 | biostudies-literature
Project description:Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. Quantification of CD3 tumor-infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in biopsy tissues taken at diagnosis reveal a spectrum of immunologically "cold" to "hot" tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.
| S-EPMC8858331 | biostudies-literature
Project description:BackgroundTumor progression is accompanied by dramatic remodeling of the surrounding extracellular matrix leading to the formation of a tumor-specific ECM, which is often more collagen-rich and of increased stiffness. The altered ECM of the tumor supports cancer growth and metastasis, but it is unknown if this effect involves modulation of T cell activity. To investigate if a high-density tumor-specific ECM could influence the ability of T cells to kill cancer cells, we here studied how T cells respond to 3D culture in different collagen densities.MethodsT cells cultured in 3D conditions surrounded by a high or low collagen density were imaged using confocal fluorescent microscopy. The effects of the different collagen densities on T cell proliferation, survival, and differentiation were examined using flow cytometry. Cancer cell proliferation in similar 3D conditions was also measured. Triple-negative breast cancer specimens were analyzed for the number of infiltrating CD8+ T cells and for the collagen density. Whole-transcriptome analyses were applied to investigate in detail the effects of collagen density on T cells. Computational analyses were used to identify transcription factors involved in the collagen density-induced gene regulation. Observed changes were confirmed by qRT-PCR analysis.ResultsT cell proliferation was significantly reduced in a high-density matrix compared to a low-density matrix and prolonged culture in a high-density matrix led to a higher ratio of CD4+ to CD8+ T cells. The proliferation of cancer cells was unaffected by the surrounding collagen-density. Consistently, we observed a reduction in the number of infiltrating CD8+ T-cells in mammary tumors with high collagen-density indicating that collagen-density has a role in regulating T cell abundance in human breast cancer. Whole-transcriptome analysis of 3D-cultured T cells revealed that a high-density matrix induces downregulation of cytotoxic activity markers and upregulation of regulatory T cell markers. These transcriptional changes were predicted to involve autocrine TGF-β signaling and they were accompanied by an impaired ability of tumor-infiltrating T cells to kill autologous cancer cells.ConclusionsOur study identifies a new immune modulatory mechanism, which could be essential for suppression of T cell activity in the tumor microenvironment.
| S-EPMC6417085 | biostudies-literature