https://cancerbiologyprogram.med.wayne.edu/pdfs/hallmarks_cancer_article.pdf

Hallmarks of cancer: the next generation.

There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters The analysis module and visualization module were combined into a reusable workflow Currently, clusterProfiler supports three species, including humans, mice, and yeast Methods provided in this package can be easily extended to other species and ontologies The clusterProfiler package is released under Artistic-20 License within Bioconductor project The source code and vignette are freely available at http://bioconductororg/packages/release/bioc/html/clusterProfilerhtml

/pdf/clusterprofiler-an-r-package-for-comparing-biological-themes-xbzzr3fbnj.pdf

clusterProfiler: an R Package for Comparing Biological Themes Among Gene Clusters

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

Les cellules B et les structures lymphoïdes tertiaires intra-tumorales sont des marqueurs de survie et de réponse à l’immunothérapie

Soft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of non-pediatric solid tumors. Recent clinical trials with check-point blockade immunotherapies reported a response in up to 15% of patients, but there are no biomarkers predicting response of STS to checkpoint blockade therapies yet. We analyzed transcriptomic data of publicly available cohorts, accounting for more than 600 complex genomic STS, including leiomyosarcoma (LMS, 35.4%), dedifferentiated liposarcoma (DDLPS, 33.9%) and undifferentiated pleomorphic sarcoma (UPS, 30.8%). Using a deconvolution method to estimate the tumor microenvironment composition with accurate scores depicting the immune profile of tumors, we established a robust immune classification that is consistent through different datasets. We divided the patients into 5 Sarcoma Immune Classes, labelled A1, A2, B, C1 and C2, which exhibit different extents and composition of immune infiltrate. Two groups (A1: 23.3% and A2: 27.1% of all tumors) exhibit a very low to low immune infiltrate for all cell types. Another class (B: 14.5% of all tumors) displays moderate immune infiltrate and a strong presence of endothelial cells. Finally, the remaining two groups (C1: 19.4% and C2: 15.6%) are highly infiltrated by all immune cell types. All histologies were found in all five immune classes, although LMS were enriched in classes A1 and A2. The immune-high groups exhibit a significantly prolonged overall survival compared to the other groups. Notably, the immune high group C2 is characterized by an extremely rich immune infiltrate containing both lymphocytes and myeloid cells, and is associated with a striking overexpression of several immune checkpoints genes: PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), LAG3, HAVCR2 (TIM-3), CTLA4. This group also contains tumors with a strong expression of the B cell attractant chemokine CXCL13, often associated with the presence of tertiary lymphoid structures (TLS). We validated the relevance of TLS as a biomarker of this group by quantitative immunohistochemistry (IHC) using stainings for CD3, DC-Lamp, CD8, and CD20 on a 95-patient STS cohort (LMS, 34%; DDLPS, 33%; UPS, 34%). Tumors with visible TLS had a higher density of CD3+, CD8+ and CD20+ cells in the tumor core and the invasive margin, hence showing the possibility to identify the immune-high group by using IHC. The expression of immune checkpoint molecules was also detected by multiplex immunofluorescence for CD3, CD20, PD-1 and Lag3 in these tumors, confirming the presence of checkpoint molecules in the immune-high group. To check whether the immune-high group C2 was associated with enhanced response to checkpoint blockade therapy, we intend to analyze tumors from a recently published phase 2 clinical trial in which patients underwent treatment with anti-PD-1 pembrolizumab. Citation Format: Florent Petitprez, Tom Wei-Wu Chen, Cheng-Ming Sun, Julien Calderaro, Li-Ping Hsiao, Laetitia Lacroix, Ivo Natario, Maud Toulmonde, Carlo Lucchesi, Yec9han Laizet, Antoine Italiano, Aurelien de Reynies, Catherine Sautes-Fridman, Wolf H. Fridman. A novel transcriptomic-based immune classification of soft tissue sarcoma (STS) and its association with molecular characteristics, clinical outcome and response to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4045.

Abstract 4045: A novel transcriptomic-based immune classification of soft tissue sarcoma (STS) and its association with molecular characteristics, clinical outcome and response to therapy

Analysis of five monoclonal autoantibodies, rheumatoid factors produced by hybridomas generated from spleen cells of BALB/c mice repeatedly infected with A/PR/8/34 human influenza A virus, revealed that they recognized distinct but spatially related epitopes. The differing isoallotypic specificity of the IgM and IgA monoclonal antibodies correlated with the presence of Ile258 and Ala305, respectively. Although these data suggest that the epitopes recognized are within the CH2 domain, all antibodies failed to inhibit IgG antigen reactivity with Staphylococcus aureus protein A (SpA), C1q, mouse C3, human Fc gamma RI or mouse Fc gamma RII, activities known to be predominantly determined by CH2 domain structures. Reactivity of the IgA antibody, Z34, with IgG2b allowed further specificity studies using a panel of 26 mutant IgG2b proteins, each having single amino acid replacements over the surface of the CH2 domain. The only substitution that affected Z34 reactivity was Asn/Ala297, which destroyed the glycosylation sequon, resulting in secretion of an aglycosylated IgG molecule. The epitope recognized by Z34 therefore seems to be located outside of the Fc gamma R and C1q binding sites, but to be dependent on the presence of carbohydrate for expression. In contrast to the binding studies, complement activation by aggregated IgG2a, through classical or alternative pathways, was inhibited by the presence of autoantibodies. The functional significance of isotype-specific autoantibody in immune regulation is discussed.

Activation of effector functions by immune complexes of mouse IgG2a with isotype-specific autoantibodies

Problems and prospects of new immunotherapeutic approaches.

EFIS‐EJI Ruggero Ceppelini Advanced Immunology School Course: Tumour immunology 2017: From tissue microenvironment to immunotherapy. Naples 16–18 October 2017

Wolf H. Fridman

Papers

Les cellules B et les structures lymphoïdes tertiaires intra-tumorales sont des marqueurs de survie et de réponse à l’immunothérapie

Abstract 4045: A novel transcriptomic-based immune classification of soft tissue sarcoma (STS) and its association with molecular characteristics, clinical outcome and response to therapy

Activation of effector functions by immune complexes of mouse IgG2a with isotype-specific autoantibodies

Problems and prospects of new immunotherapeutic approaches.

EFIS‐EJI Ruggero Ceppelini Advanced Immunology School Course: Tumour immunology 2017: From tissue microenvironment to immunotherapy. Naples 16–18 October 2017