High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer

Abstract Background Characterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells. The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed. Methods We identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry. Results IRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8+ T cell infiltration and tumoral IRF8 expression. Conclusions We propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8+ T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.

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Correction to: High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer

Breast Cancer Research ◽

10.1186/s13058-021-01427-6 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Gerardo Gatti ◽

Courtney Betts ◽

Darío Rocha ◽

Maribel Nicola ◽

Verónica Grupe ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Therapy Response ◽

Predictive Biomarker ◽

Cd8 T Cell ◽

Cell Infiltration ◽

T Cell Infiltration

An amendment to this paper has been published and can be accessed via the original article.

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Pilose antler polypeptides promote chemosensitization and T-cell infiltration of triple-negative breast cancer

Journal of Functional Foods ◽

10.1016/j.jff.2021.104664 ◽

2021 ◽

Vol 85 ◽

pp. 104664

Author(s):

Mohan Li ◽

Kexin Zheng ◽

Shiliang Ma ◽

Pengpeng Hu ◽

Bo Yuan ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cell Infiltration ◽

T Cell Infiltration

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Abstract 2439: Association of antigen processing machinery components and CD8+ T-cell infiltration in breast cancer brain metastasis

10.1158/1538-7445.am2011-2439 ◽

2011 ◽

Author(s):

Yan Liu ◽

Yoshihiro Komohara ◽

Natalie Domenick ◽

Craig Horbinski ◽

Ronald Hamilton ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Brain Metastasis ◽

Antigen Processing ◽

Cd8 T Cell ◽

Cell Infiltration ◽

Antigen Processing Machinery ◽

Processing Machinery ◽

T Cell Infiltration ◽

Breast Cancer Brain Metastasis

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CD8+ cytotoxic T cell and FOXP3+ regulatory T cell infiltration in relation to breast cancer survival and molecular subtypes

Breast Cancer Research and Treatment ◽

10.1007/s10549-011-1647-3 ◽

2011 ◽

Vol 130 (2) ◽

pp. 645-655 ◽

Cited By ~ 159

Author(s):

Fangfang Liu ◽

Ronggang Lang ◽

Jing Zhao ◽

Xinmin Zhang ◽

Gordon A. Pringle ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Regulatory T Cell ◽

Cancer Survival ◽

Molecular Subtypes ◽

Breast Cancer Survival ◽

Cell Infiltration ◽

Cytotoxic T Cell ◽

T Cell Infiltration

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Higher cytolytic score correlates with an immunosuppressive tumor microenvironment and reduced survival in glioblastoma

Scientific Reports ◽

10.1038/s41598-020-73793-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Alexander F. Haddad ◽

Jia-Shu Chen ◽

Taemin Oh ◽

Matheus P. Pereira ◽

Rushikesh S. Joshi ◽

...

Keyword(s):

T Cell ◽

Immune Cell ◽

Cell Types ◽

Cd8 T Cell ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Sequencing Data ◽

Gene Score ◽

T Cell Infiltration ◽

The Relationship

Abstract Cytolytic score (CYT), calculated from mRNA expression levels of granzyme and perforin, positively correlates with CD8+ T cell infiltration/activity in a variety of cancers. Unlike other cancers, higher CYT has been associated with worse prognosis in glioblastoma (GBM). To address this discrepancy, we sought to investigate the relationship between CYT and immune checkpoint gene score (ICGscore), as well as their correlation with patient survival and tumor immune cell infiltration. Clinical and RNA-sequencing data for patients with newly diagnosed GBM were obtained from The Cancer Genome Atlas. Maximally-selected rank statistics was used to dichotomize subgroups. CIBERSORT was used to estimate abudence of immune cell-types. Spearman correlation was used to characterize the relationship between CYT and ICGscore. Kaplan–Meier curves were generated for survival analysis. Overall, 28/151 patients had high CYT. High CYT was associated with a mesenchymal subtype (p < 0.001) and worse survival (7.45 vs. 12.2 months, p < 0.001). There were no differences in patient demographics, IDH/MGMT mutation status, or treatment. On subgroup analysis, patients with high CYT/ICGscore had significantly increased CD8+ infiltration (p < 0.001), as expected, and worse survival (HR 0.445, p < 0.01). Furthermore, CYT strongly correlated with ICGscore (RS = 0.675, p < 0.001). The high CYT/ICGscore subgroup was associated with greater infiltration of M2 macrophages (p = 0.011) and neutrophils (p = 0.055). Our study highlights a multidimensional immunosuppressive GBM microenvironment in patients with higher CYT and potentially identifies patients with high CYT/ICGscore as a subgroup that may particularly benefit from multi-faceted immunotherapies, given their already elevated tumor CD8+ T cell levels.

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The Role of PTEN Loss in Immune Escape, Melanoma Prognosis and Therapy Response

Cancers ◽

10.3390/cancers12030742 ◽

2020 ◽

Vol 12 (3) ◽

pp. 742 ◽

Cited By ~ 2

Author(s):

Rita Cabrita ◽

Shamik Mitra ◽

Adriana Sanna ◽

Henrik Ekedahl ◽

Kristina Lövgren ◽

...

Keyword(s):

T Cell ◽

Metastatic Melanoma ◽

Immune Evasion ◽

Immune Escape ◽

Therapy Response ◽

Predictive Biomarkers ◽

Cell Infiltration ◽

Pten Gene ◽

T Cell Infiltration

Checkpoint blockade therapies have changed the clinical management of metastatic melanoma patients considerably, showing survival benefits. Despite the clinical success, not all patients respond to treatment or they develop resistance. Although there are several treatment predictive biomarkers, understanding therapy resistance and the mechanisms of tumor immune evasion is crucial to increase the frequency of patients benefiting from treatment. The PTEN gene is thought to promote immune evasion and is frequently mutated in cancer and melanoma. Another feature of melanoma tumors that may affect the capacity of escaping T-cell recognition is melanoma cell dedifferentiation characterized by decreased expression of the microphtalmia-associated transcription factor (MITF) gene. In this study, we have explored the role of PTEN in prognosis, therapy response, and immune escape in the context of MITF expression using immunostaining and genomic data from a large cohort of metastatic melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T-cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T-cell infiltration, and transcriptional properties rendering them resistant to targeted- and immuno-therapy.

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