Programmed Death Ligand 2 in Cancer-Induced Immune Suppression

Inhibitory molecules of the B7/CD28 family play a key role in the induction of immune tolerance in the tumor microenvironment. The programmed death-1 receptor (PD-1), with its ligands PD-L1 and PD-L2, constitutes an important member of these inhibitory pathways. The relevance of the PD-1/PD-L1 pathway in cancer has been extensively studied and therapeutic approaches targeting PD-1 and PD-L1 have been developed and are undergoing human clinical testing. However, PD-L2 has not received as much attention and its role in modulating tumor immunity is less clear. Here, we review the literature on the immunobiology of PD-L2, particularly on its possible roles in cancer-induced immune suppression and we discuss the results of recent studies targeting PD-L2 in cancer

The efficacy of combining CTLA-4 blockade with gemcitabine critically depends on timing.

<p>(A) Tumor area in mm² (mean ± SD) of AB1-HA tumors that were injected on day 0, mice (n = 86) were treated with different schedules of anti-CTLA4 and gemcitabine (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0061895#pone.0061895.s002" target="_blank">Figure S2</a>), or with PBS (pooled data of 3 separate experiments are shown). (B) Kaplan-Meier survival plot of the same experiment.</p

Combination of CTLA-4 blockade and gemcitabine chemotherapy results in synergistic anti-tumor effect.

<p>(A) Tumor surface in mm² (mean ± SD) of AB1-HA tumors that were injected on day 0, mice (n = 87) were treated on day 9/12/15/18 with 75 µg anti-CTLA-4 and with 120 µg/g gemcitabine on day 9/12/15/18/21, or with PBS (pooled data of 5 separate experiments are shown). (B) Kaplan-Meier survival plot of the same experiment. (C) Tumor surface in mm² (mean ± SD) of AB1-HA tumors that were injected on day 0, mice (n = 65) were treated on day 9 with 200 µg anti-CTLA-4 and 6 µg/g cisplatin, or with PBS (pooled data from 3 separate experiments are shown). (D) Kaplan-Meier survival plot of the same experiment.</p

Combination of CTLA-4 blockade and gemcitabine chemotherapy results in the induction of protective T cell memory.

<p>(A) Kaplan-Meier survival plot of mice that had been cured by either anti-CTLA-4 alone or combination therapy and that were subsequently rechallenged with AB1 mesothelioma cells, showing protective immunity in 80% and 92% respectively. T cell subset analysis in tumor-draining lymph nodes in these mice (*p<0.05; **p<0.01***p<0.001): CD44⁺/CD62L⁺/CD4⁺ T central memory cells (B); CD44⁺/CD62L^−/CD4⁺ T effector memory cells (C); CD44⁺/CD62L⁺/CD8⁺ T central memory cells (D); CD44⁺/CD62L^−/CD8⁺ T effector memory cells (E).</p

Characterization of a novel breast cancer cell line derived from a metastatic bone lesion of a breast cancer patient

We aimed to generate and characterize a novel cell line from a breast cancer bone metastasis to better study the progression of the disease.The cell line, P7731, was derived from a metastatic bone lesion of a breast cancer patient and assessed for marker expression. P7731 was analyzed for DNA copy number variation, somatic mutations, and gene expression and was compared with the primary tumor.P7731 cells are negative for estrogen receptor alpha (ERα), progesterone receptor (PR), and HER2 (triple-negative); strongly express vimentin (100% of cells positive) and also express cytokeratins 8/18 and 19 but at lower frequencies. Flow cytometry indicates P7731 cells are predominantly CD44/CD49f/EpCAM, consistent with a primitive, mesenchymal-like phenotype. The cell line is tumorigenic in immunocompromised mice. Exome sequencing identified a total of 45 and 76 somatic mutations in the primary tumor and cell line, respectively, of which 32 were identified in both samples and included mutations in known driver genes PIK3CA, TP53, and ARID1A. P7731 retains the DNA copy number alterations present in the matching primary tumor. Homozygous deletions detected in the cell line and in the primary tumor were found in regions containing three known (CDKN2A, CDKN2B, and CDKN1B) and 23 putative tumor suppressor genes. Cell line-specific gene amplification coupled with mRNA expression analysis revealed genes and pathways with potential pro-metastatic functions.This novel human breast cancer-bone metastasis cell line will be a useful model to study aspects of breast cancer biology, particularly metastasis-related changes from breast to bone

Multidimensional phenotyping of breast cancer cell lines to guide preclinical research

Cell lines are extremely useful tools in breast cancer research. Their key benefits include a high degree of control over experimental variables and reproducibility. However, the advantages must be balanced against the limitations of modelling such a complex disease in vitro. Informed selection of cell line(s) for a given experiment now requires essential knowledge about molecular and phenotypic context in the culture dish.We performed multidimensional profiling of 36 widely used breast cancer cell lines that were cultured under standardised conditions. Flow cytometry and digital immunohistochemistry were used to compare the expression of 14 classical breast cancer biomarkers related to intrinsic molecular profiles and differentiation states: EpCAM, CD24, CD49f, CD44, ER, AR, HER2, EGFR, E-cadherin, p53, vimentin, and cytokeratins 5, 8/18 and 19.This cell-by-cell analysis revealed striking heterogeneity within cultures of individual lines that would be otherwise obscured by analysing cell homogenates, particularly amongst the triple-negative lines. High levels of p53 protein, but not RNA, were associated with somatic mutations (p\ua0=\ua00.008). We also identified new subgroups using the nanoString PanCancer Pathways panel (730 transcripts representing 13 canonical cancer pathways). Unsupervised clustering identified five groups: luminal/HER2, immortalised ('normal'), claudin-low and two basal clusters, distinguished mostly by baseline expression of TGF-beta and PI3-kinase pathway genes.These features are compared with other published genotype and phenotype information in a user-friendly reference table to help guide selection of the most appropriate models for in vitro and in vivo studies, and as a framework for classifying new patient-derived cancer cell lines and xenografts

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P &lt; 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

Abstract The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P &lt; 5.82 × 10−6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology