Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer

Dong, Di; Yie, Shang-mian; Li, Ké; Li, Fanghua; Xu, Yin; Xu, Gang; Li, Song; Zhang, Pengcheng

doi:10.1016/j.humimm.2012.07.321

Cited by 29 publications

(30 citation statements)

References 31 publications

(38 reference statements)

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“…Another suggests that high Treg levels are preferentially associated with the basal phenotype, although high Treg infiltration correlated with shorter survival for HER-2 + , luminal, and basal-type breast cancers [14]. A third study suggests that luminal breast cancers are more likely to contain large numbers of TILs than non-luminal breast cancers [15,16]. Complementing these findings, medullary breast cancer is a histologic subtype of invasive breast cancer characterized by large anaplastic tumor cells and an associated dense inflammatory infiltrate.…”

Section: Discussionmentioning

confidence: 99%

Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

et al. 2013

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Tumor infiltrating lymphocytes (TILs) convey clinically relevant information for primary breast cancers (PBCs). However, limited data characterizing the immunobiology of metastatic breast cancers (MBCs) are available. Here, we examine TILs in surgically resected MBCs relative to their matched PBCs. Tissue microarrays of PBCs and MBCs were labeled for CD3 (total T -cells), CD4 (helper T-cells), CD8 (cytotoxic T-cells), FoxP3 (regulatory T-cells), and CD20 (B-cells) to characterize TILs. Expression of estrogen receptor (ER), progesterone receptor (PR) and HER-2 classified the tumors as luminal (ER+/PR+/HER-2−), triple negative (ER−/PR−/HER-2−), or HER-2+ (ER−/PR−/HER-2+). These analyses reveal five novel findings. First, MBCs overall contained fewer TILs (mean 35.1 CD3+ TILs/HPF) than their matched PBCs (mean 23.6 CD3+ TILS/HPF), with fewer CD20+ cells than CD3+ cells in PBC and MBC (p=0.0247). Second, the number of CD3+, CD8+, CD4+, and FoxP3 TILs were decreased in triple negative MBCs relative to matched PBCs, whereas only CD8+ TILs were decreased in luminal MBCs relative to matched PBCs. Third, triple negative MBCs contain fewer TILS (mean 16 CD3+ TILs/HPF) than luminal MBCs (mean 21.7 CD3+ TILs/HPF). Fourth, brain metastases contained fewer TILs relative to MBC from other sites. Finally, in this series a CD8+/FoxP3+ T-cell ratio ≥3 in PBCs was associated with improved overall survival from diagnosis, whereas a CD8+/FoxP3+ T-cell ratio <3 in MBCs at first relapse was associated with improved overall survival. These findings suggest that evaluating the immunologic microenvironment of both PBCs and MBCs may yield important clinical information to guide breast cancer prognosis and therapy.

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Section: Discussionmentioning

confidence: 99%

Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

et al. 2013

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“…The tumour immunosurveillance hypothesis postulates that malignantly transformed cells display altered 'self-antigens' that enable the immune response to recognize and eradicate them during the early stages of tumour development [43]. Antigen recognition by CTLs requires presentation of antigenic peptides by MHC I (human leucocyte antigen (HLA-A, HLA-B, HLA-C)) molecules, whereas antigenic peptides presented by MHC II (HLA-DR, HLA-DP, HLA-DQ) are recognized by Th cells [48]. MHC II antigen expression is limited to antigenpresenting cells (APCs) in the tumour microenvironment.…”

Section: Mechanisms Of Immunity Generation and Suppression In Breast mentioning

confidence: 99%

Tumour-Infiltrating Lymphocytes (TILs) in Breast Cancer: a Predictive or a Prognostic Marker?

Dushyanthen

Savas

Willard-Gallo

et al. 2015

Curr Breast Cancer Rep

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Breast cancer has not been considered as an immunogenic solid cancer type; however, recent studies demonstrate evidence of significant prognostic information that can be derived from immune cell infiltration via tumourinfiltrating lymphocytes (TILs) in patient tumours. The presence of TILs has been associated with increased response rates to cytotoxic chemotherapy as well as targeted therapies, leading to improved disease-free and overall survival in certain breast cancer subtypes. Accordingly, experts have developed a standardized methodology for evaluating TILs within clinical specimens in histopathological practice. An overview of a newly established practical guideline for TIL evaluation in breast cancer is described in this paper. Furthermore, this review discusses the predictive and prognostic significance of TILs, highlighting recent evidence linking TILs to prognosis in breast cancer. In addition, it summarizes the most current understanding of TIL composition as well as mechanisms of immunity generation and suppression. Overall, the current literature demonstrates that TILs are proving to be a promising target for the treatment of immunogenic breast cancers.

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“…Although HLA-G expression has been documented in several other cancer sites, i.e. cervical cancer [15,34-37], melanoma [49-51], breast [49,52-54], colorectal [55-57], gastric [57-60], esophageal [57,61,62], lung [57,63,64], and other cancers [49], the implications of HLA-G methylation on the expression of the protein have not been described.…”

Section: Discussionmentioning

confidence: 99%

Case–control study of HLA-G promoter methylation status, HPV infection and cervical neoplasia in Curitiba, Brazil: a pilot analysis

et al. 2012

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BackgroundThe causal association between persistent human papillomavirus (HPV) infection and cervical cancer has been established, but the mechanisms that favor HPV persistence in cervical cells are still unknown. The diminished capability of the immune system to control and resolve HPV infection is one of several hypotheses. The tolerogenic protein HLA-G has shown aberrant expression in a variety of cancers, which has been suggested as a mechanism for tumor escape from immunosurveillance. In the present study we evaluate the role of epigenetic modification (promoter de-methylation) of the HLA-G gene on susceptibility to HPV infection and development of high-grade cervical lesions.MethodsA case–control study was carried out in Curitiba, Brazil, between February and June 2010. A total of 789 women aged 15–47 years were recruited: 510 controls with normal cervical cytology, and 279 cases with histologically confirmed cervical intraepithelial neoplasia grade 2 (CIN2, N = 150) or grade 3 (CIN3, N = 129). All women were administered a questionnaire by interview, which collected information on demographic and lifestyle factors, and a cervical sample was collected. HPV DNA detection was performed by GP5+/GP6+ primer-mediated PCR. HPV-positive samples were genotyped by multiplex PCR. A pilot analysis of HLA-G promoter methylation was carried out in a subset of the study population (96 cases and 76 controls) by pyrosequencing. HLA-G methylation and HPV infection status of cases and controls were compared, and confounding factors were computed by t Student and non-parametric Wilcoxon tests. Comparison of HLA-G methylation between cases and controls was assessed by the Bonferroni correction. The association of HLA-G methylation with CIN2/3 was evaluated by logistic regression.ResultsHPV prevalence was 19.6% in controls and 94.3% in CIN2/3 cases. HPV16, 31, 33, 35 and 18 were the most prevalent types. Methylation analysis of seven CpGs in the HLA-G promoter did not reveal any spontaneous de-methylation events in CIN2/3 cases (mean proportion of methylation: 75.8%) with respect to controls (mean 73.7%; odds ratio 1.01, 95% confidence interval 0.96, 1.07).ConclusionsThis study did not support the hypothesis that spontaneous de-methylation events in the HLA-G promoter play a primary role in promoting escape from immunosurveillance in the development of precancerous cervical lesions.

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Importance of HLA-G expression and tumor infiltrating lymphocytes in molecular subtypes of breast cancer

Cited by 29 publications

References 31 publications

Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study

Tumour-Infiltrating Lymphocytes (TILs) in Breast Cancer: a Predictive or a Prognostic Marker?

Case–control study of HLA-G promoter methylation status, HPV infection and cervical neoplasia in Curitiba, Brazil: a pilot analysis

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