PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas

Cimino‐Mathews, Ashley; Thompson, Elizabeth D.; Taube, Janis M.; Ye, Xiaobu; Yao, Lu; Meeker, Alan K.; Xu, Huimin; Sharma, Rajni; Lecksell, Kristen; Cornish, Toby C.; Cuka, Nathan; Argani, Pedram; Emens, Leisha A.

doi:10.1016/j.humpath.2015.09.003

Cited by 306 publications

(279 citation statements)

References 36 publications

Supporting

Mentioning

252

Contrasting

Order By: Relevance

“…Immune cell PD-L1 expression in invasive breast carcinoma is more common than tumor cell PD-L1 expression, is associated with high-risk histological features such as tumor grade, and is more common in triple-negative carcinomas (15,(32)(33)(34). In our cohort of pure DCIS, we identified associations between It is not yet conclusively known why some breast carcinomas have higher TILs than others.…”

Section: Discussionmentioning

confidence: 76%

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown.Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n ¼ 55) and mutation data (n ¼ 20).Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P ¼ 0.002/0.035), ER-negative (P ¼ 0.02/0.02), and ERBB2-amplified tumors (P < 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P < 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P ¼ 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P < 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels.Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res; 23(17); 5210-7.Ó2017 AACR.

show abstract

Section: Discussionmentioning

confidence: 76%

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Hendry

Pang

Byrne

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…In particular, overexpression of the B7-CD28 gene family members (PD-1/PD-L1, CD80/CTLA4 among others), which are known to negatively regulate T-cell activation (37)(38)(39)(40), was also found in immune active samples. It is in line with a recent report, showing that PD-1 þ T infiltrating lymphocytes and PD-L1 þ tumor cells were both favorable prognostic factors in ovarian cancer (41).…”

Section: Discussionmentioning

confidence: 99%

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

Kreuzinger

Geroldinger

Smeets

et al. 2017

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC. Experimental Design: Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC. Results: Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens, CEACAM21, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones. Conclusions: The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications. Clin Cancer Res; 23(24); 7621–32. ©2017 AACR.

show abstract

“…[18][19][20][21][22][23][24] We assessed genomic alterations in the 10 B7 family members across multiple cancer types using cBioPortal and TCGA. B7 family members showed higher levels of amplification in lung and ovarian cancer, but particularly in breast cancer, with more than 50% of patients having at least one B7 family gene amplification.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

Shen

Wang

et al. 2016

OncoImmunology

View full text Add to dashboard Cite

The B7 gene family has crucial roles in the regulation of adaptive cellular immunity. In cancer, deregulation of co-inhibitory B7 molecules is associated with reduced antitumor immunity and cancer immune evasion. FDA approval of cancer immunotherapy antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1)-both ligands of the B7 family-demonstrate the impact of these checkpoint regulators in cancer. Using data from cBioPortal, we performed comprehensive molecular profiling of the 10 currently known B7 family proteins in 105 different cancers. B7 family members were amplified in breast cancer: with B7 mRNA levels upregulated in a cohort of 1,098 patients with all types of breast cancer and in 82 patients with triple-negative breast cancer. Promoter methylation analysis indicated an epigenetic basis for deregulation of certain B7 family genes in breast cancer. Moreover, patients with B7-H6 genomic alterations had significantly worse overall survival, and certain clinical attributes were associated with B7-H6 expression, which indicates that B7-H6 may be a potential target for breast cancer immunotherapy. Finally, using network analysis (based on data from cBioportal), we identified BTLA, MARCH8, PLSCR1 and SMAD3 as potentially involved in T cell signaling under regulation of B7 family proteins.

show abstract

PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas

Cited by 306 publications

References 36 publications

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer

Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer

Contact Info

Product

Resources

About