B7-H3 and B7-H4 expression in phyllodes tumors of the breast detected by RNA in situ hybridization and immunohistochemistry: Association with clinicopathological features and T-cell infiltration

Phyllodes tumors are rare biphasic breast tumors with the potential for both local recurrence and distant metastasis. The aberrant expression of B7-H3 and B7-H4 B7 molecules could be potential targets for future development of immunotherapeutic approaches. This work was undertaken to evaluate the expression of B7-H3 and B7-H4 in phyllodes tumors and assess the association with the grade and clinical behavior of phyllodes tumors. In addition, the roles of B7-H3 and B7-H4 in the regulation of tumor immune surveillance were evaluated by assessing the relationship between B7-H3/B7-H4 expression and T-cell infiltration. The messenger RNA and protein expression of B7-H3/B7-H4 were determined by RNAscope in situ hybridization and immunohistochemistry, respectively, in 101 phyllodes tumors (60 benign, 26 borderline, and 15 malignant) using a tissue microarray. Immunohistochemistry for CD3 and CD8 was also performed. B7-H3 messenger RNA and protein appeared to be concentrated mainly in the stromal compartment of phyllodes tumors. However, B7-H4 messenger RNA and protein were undetectable in the stromal compartment of phyllodes tumors. Stromal B7-H3 messenger RNA and protein expression were noted in 10 (16.7%) and 31 (51.7%) of 60 benign phyllodes tumors, 12 (46.1%) and 20 (76.9%) of 26 borderline phyllodes tumors, and 10 (66.7%) and 13 (86.7%) of 15 malignant phyllodes tumors, respectively. Stromal B7-H3 messenger RNA and protein expression increased as phyllodes tumors progressed from benign to borderline and finally to the malignant grade (Pearson’s R = 0.411, p < 0.001 and Pearson’s R = 0.293, p = 0.003, respectively). The recurrence rate was higher in the stromal B7-H3 messenger RNA or protein-positive group than in the negative group, but this difference was not significant. Stromal B7-H3 protein expression inversely correlated with the densities of CD3+ and CD8+ T-cell infiltrates ( p = 0.001 and p = 0.027, respectively). These results suggest that B7-H3 is involved in the progression of phyllodes tumors and may contribute to their immune surveillance.

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B7-H3 and B7-H4 expression in ductal carcinoma in situ of the breast detected with RNA in situ hybridization and immunohistochemistry and its association with clinicopathologic features and T-cell infiltration

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2018.10.154 ◽

2019 ◽

Vol 45 (2) ◽

pp. e36

Author(s):

J.S. Lee ◽

N.I. Kim ◽

G.E. Kim ◽

M.H. Park ◽

J.H. Yoon

Keyword(s):

In Situ Hybridization ◽

T Cell ◽

Ductal Carcinoma In Situ ◽

Carcinoma In Situ ◽

Ductal Carcinoma ◽

Cell Infiltration ◽

Clinicopathologic Features ◽

T Cell Infiltration ◽

Rna In Situ Hybridization

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OTME-20. Chitinase-3-like-1(CHI3L1) Protein Complexes Regulate the immunosuppressive Microenvironment in Glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.071 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii17-ii18

Author(s):

Apeng Chen ◽

Yinan Jiang ◽

Zhengwei Li ◽

Xiangwei Xiao ◽

Dean Yimlamai ◽

...

Keyword(s):

T Cell ◽

Immune Evasion ◽

Protein Complexes ◽

Immune Surveillance ◽

Cell Infiltration ◽

Binding Motif ◽

T Cell Infiltration ◽

Pathway Activation ◽

Galectin 3 ◽

Immunosuppressive Microenvironment

Abstract Glioblastoma (GBM) is the most common and highly malignant brain tumor in adults. Despite advances in multimodal treatment, GBM remains largely incurable. While immunotherapies have been highly effective in some types of cancer, the disappointing results from clinical trials for GBM immunotherapy represent continued challenges. GBM is highly immunosuppressive and resistant to immunotherapy because of glioma cells escaping from immune surveillance by reprograming the tumor microenvironment (TME). However, understanding the mechanisms of immune evasion by GBM remains elusive. Based on unbiased approaches, we found that Chitinase-3-like-1 (CHI3L1), also known as human homolog YKL-40, is highly expressed in GBM, which is regulated by the CHI3L1-PI3K/AKT/mTOR signaling in a positive feedback loop. Gain- and loss-function studies reveal that CHI3L1 plays a predominant role in regulating an immunosuppressive microenvironment by reprogramming tumor-associated macrophages (TAMs). Using the liquid chromatography-mass spectrometry and orthogonal structure-based screening, we found that Galectin-3 binding protein (Gal3BP) and its binding partner, Galectin-3 (Gal3), can interact competitively with the same binding motif on CHI3L1, leading to selective migration of M2-like versus M1-like bone marrow-derived macrophages (BMDMs) and resident microglia (MG). Mechanistically, the CHI3L1-Gal3 protein complex governs a transcriptional program of NFκB/CEBPβ to control the protumor phenotype of BMDMs, leading to inhibition of T cell infiltration and activation in the GBM TME. However, Gal3BP can reverse CHI3L1-Gal3 induced signaling pathway activation and subsequent protumor phenotype in TAMs. Based on protein binding motifs, a newly developed Gal3BP mimetic peptide can attenuate immune suppression and tumor progression in the syngeneic GBM mouse models, including decreasing M2-like TAMs and increasing M1-like TAMs and T cell infiltration. Together, these results shed light on the role of CHI3L1 protein complexes in immune evasion by glioblastoma and as a potential immunotherapeutic target for this devastating disease.

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Arf1-mediated lipid metabolism sustains cancer cells and its ablation induces anti-tumor immune responses in mice

Nature Communications ◽

10.1038/s41467-019-14046-9 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 4

Author(s):

Guohao Wang ◽

Junji Xu ◽

Jiangsha Zhao ◽

Weiqin Yin ◽

Dayong Liu ◽

...

Keyword(s):

Lipid Metabolism ◽

T Cell ◽

Immune Responses ◽

Cancer Cells ◽

Immune Surveillance ◽

Therapeutic Vaccine ◽

Treatment Resistance ◽

Inverse Correlation ◽

Cell Infiltration ◽

T Cell Infiltration

AbstractCancer stem cells (CSCs) may be responsible for treatment resistance, tumor metastasis, and disease recurrence. Here we demonstrate that the Arf1-mediated lipid metabolism sustains cells enriched with CSCs and its ablation induces anti-tumor immune responses in mice. Notably, Arf1 ablation in cancer cells induces mitochondrial defects, endoplasmic-reticulum stress, and the release of damage-associated molecular patterns (DAMPs), which recruit and activate dendritic cells (DCs) at tumor sites. The activated immune system finally elicits antitumor immune surveillance by stimulating T-cell infiltration and activation. Furthermore, TCGA data analysis shows an inverse correlation between Arf1 expression and T-cell infiltration and activation along with patient survival in various human cancers. Our results reveal that Arf1-pathway knockdown not only kills CSCs but also elicits a tumor-specific immune response that converts dying CSCs into a therapeutic vaccine, leading to durable benefits.

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