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

The discovery of Toll-like receptors (TLRs) as components that recognize conserved structures in pathogens has greatly advanced understanding of how the body senses pathogen invasion, triggers innate immune responses and primes antigen-specific adaptive immunity. Although TLRs are critical for host defense, it has become apparent that loss of negative regulation of TLR signaling, as well as recognition of self molecules by TLRs, are strongly associated with the pathogenesis of inflammatory and autoimmune diseases. Furthermore, it is now clear that the interaction between TLRs and recently identified cytosolic innate immune sensors is crucial for mounting effective immune responses. Here we describe the recent advances that have been made by research into the role of TLR biology in host defense and disease.

/pdf/the-role-of-pattern-recognition-receptors-in-innate-immunity-39y77tlxza.pdf

The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors

Cancers develop in complex tissue environments, which they depend on for sustained growth, invasion and metastasis. Unlike tumor cells, stromal cell types within the tumor microenvironment (TME) are genetically stable and thus represent an attractive therapeutic target with reduced risk of resistance and tumor recurrence. However, specifically disrupting the pro-tumorigenic TME is a challenging undertaking, as the TME has diverse capacities to induce both beneficial and adverse consequences for tumorigenesis. Furthermore, many studies have shown that the microenvironment is capable of normalizing tumor cells, suggesting that re-education of stromal cells, rather than targeted ablation per se, may be an effective strategy for treating cancer. Here we discuss the paradoxical roles of the TME during specific stages of cancer progression and metastasis, as well as recent therapeutic attempts to re-educate stromal cells within the TME to have anti-tumorigenic effects.

/pdf/microenvironmental-regulation-of-tumor-progression-and-4528oymlw6.pdf

Microenvironmental regulation of tumor progression and metastasis.

PD-1 is an immunoinhibitory receptor expressed by activated T cells, B cells, and myeloid cells. Mice deficient in PD-1 exhibit a breakdown of peripheral tolerance and demonstrate multiple autoimmune features. We report here that the ligand of PD-1 (PD-L1) is a member of the B7 gene family. Engagement of PD-1 by PD-L1 leads to the inhibition of T cell receptor-mediated lymphocyte proliferation and cytokine secretion. In addition, PD-1 signaling can inhibit at least suboptimal levels of CD28-mediated costimulation. PD-L1 is expressed by antigen-presenting cells, including human peripheral blood monocytes stimulated with interferon gamma, and activated human and murine dendritic cells. In addition, PD-L1 is expressed in nonlymphoid tissues such as heart and lung. The relative levels of inhibitory PD-L1 and costimulatory B7-1/B7-2 signals on antigen-presenting cells may determine the extent of T cell activation and consequently the threshold between tolerance and autoimmunity. PD-L1 expression on nonlymphoid tissues and its potential interaction with PD-1 may subsequently determine the extent of immune responses at sites of inflammation.

/pdf/engagement-of-the-pd-1-immunoinhibitory-receptor-by-a-novel-2cb02kpkk5.pdf

Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation.

Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

https://science.sciencemag.org/content/sci/267/5203/1449.full.pdf

The Fas Death Factor

Cellular aspects of lymphoid differentiation: T and NK cells

Resume Les cellules NK representent le troisieme type de lymphocyte avec les lymphocytes T et B. Leur definition peut etre morphologique, phenotypique et fonctionnelle. Au niveau morphologique, ce sont de grands lymphocytes granuleux comme les lymphocytes T cytotoxiques CD8+. Au niveau phenotypique, ils se caracterisent par l'absence de recepteur pour l'antigene et par la presence d'un recepteur de basse affinite pour le fragment Fc des IgG, CD16, et d'une isoforme d'une molecule d'adherence neuronale N-CAM, CD56. Sur un plan fonctionnel, ce sont des cellules cytotoxiques capables de lyser les cellules recouvertes d'anticorps par une cytotoxicite dependante des anticorps, et de lyser egalement par un mecanisme de cytotoxicite naturelle, par exemple, des cellules infectees par des virus ou des cellules tumorales. Une nouvelle famille de recepteurs, exprimes sur des cellules NK et une sous-population de cellules T memoires, assurent une regulation negative de la cytotoxicite et de la production de cytokines de ces cellules. Ces recepteurs reconnaissent les molecules du CMH de classe I classiques et non classiques. Ils appartiennent soit a la superfamille des immunoglobulines et sont appeles KIR, soit a la superfamille des lectines de type C, et sont representes par les heterodimeres CD94-NKG2. Apres reconnaissance de leur ligand, ces recepteurs sont phosphoryles sur un residu tyrosine present dans leur partie intracytoplasmique au sein d'un motif appele ITIM (Immunoreceptor tyrosine-based inhibition motif). La phosphorylation de ce motif permet le recrutement de proteines tyrosine phosphatases SHP-1 et/ou SHP-2 responsables par leur activite enzymatique du pouvoir inhibiteur de ces recepteurs. L'etude de l'implication des cellules NK in vivo dans l'elimination des processus tumoraux et des infections microbiologiques necessite une etude plus approfondie du repertoire et de la fonctionnalite de ces recepteurs pour les molecules de classe I.

Les cellules NK

The Novel Trifunctional Anti-BCMA NK Cell Engager SAR'514 Has Potent in-Vitro and in-Vivo Anti-Myeloma Effect through Dual NK Cell Engagement

B7h6 -bindende monoklonale antikörper und ihre verwendung


 Background: Resistance to PD1/L1 immune checkpoint inhibitors (ICIs) in advanced NSCLC patients is observed in about 80% of individuals with no robust predictive biomarker yet. The PIONeeR trial (NCT03493581) aims to predict such resistances through a comprehensive multiparametric biomarkers analysis.
 Methodology: Among the >300 advanced NSCLC patients (pts) recruited in PIONeeR, we focused on the first 137 ≥2nd line ECOG PS0-1 pts treated with single-agent nivolumab, pembrolizumab or atezolizumab. Tumor tissue was collected at baseline and pts were re-biopsied at 6 weeks, and blood-sampled every cycle throughout the 24 weeks post C1D1. Response to PD1/L1 ICIs was assessed by RECIST 1.1 every 6 weeks. Immune contexture was characterized in tumor & blood of each pt through FACS for circulating immune cell subtypes quantification and endothelial activation, blood soluble factors dosage, dual- & multiplex IHC/digital pathology to quantify immune cells infiltrating the tumor, WES for TMB & ICI plasma dosage, leading to 331 measured biomarkers in addition to routine clinical parameters. Multivariable (MV) logistic regression was used to examine the association of each biomarker (controlled by sex, age, smoking status, histological type & PDL1+ Tumor Cells) with the risk of Early Progression (EP), i.e. within 3.5 months of treatment. Multivariable Cox regression analysis was conducted for association with PFS and OS.
 Results: Overall, the 137 pts were mainly male (64%), smokers (92%) and <70yrs (68%). Tumors were mainly non-squamous (79%) with >1% PDL1+ TC in 36% of the cases, and 21% of pts were still on treatment at data cut-off. Archived samples were available for 80% of pts at inclusion and re-biopsy was available in 52.9% of these cases. The median follow up was 19.8 months, 22.5% of pts did not progress at data cut-off while 62% presented EP. Tumor Cytotoxic T-cells density, especially PD1+ were lower in EP (MV OR=0.45, p=0.022); conversely, higher proportions of circulating cytotoxic T-cells and activated T-cells (HLA-DR+) were observed in EP (MV OR=3.8, p<0.001). Among other biomarkers, Tregs (MV OR=0.44, p=0.018), NK cell subsets (MV OR≤0.44, p<0.05), albumin (MV OR=0.4, p<0.01) and PDL1 TC % (MV OR=0.27, p<0.01) were decreased whereas alkaline phosphatase was increased (OR=3, p=0.018). >65% inter-pt variability was observed in plasma exposures for all ICIs, with 8-10% of pts displaying trough levels below the target engagement threshold. Data will be presented through unsupervised clustering algorithms & multi-modal supervised learning methods. Changes after 6 weeks of treatment will be analyzed to further investigate drugs mechanisms of action.
 Conclusion: The PIONeeR trial provides with the 1st comprehensive biomarkers’ analysis to establish predictive models of resistance in advanced NSCLC pts treated with PD1/L1 ICIs and highlights how tumor and circulating biomarkers are complementary.
 Citation Format: Laurent Greillier, Florence Monville, Vanina Leca, Frédéric Vely, Stephane Garcia, Joseph Ciccolini, Florence Sabatier, Gilbert Ferrani, Nawel Boudai, Lamia Ghezali, Marcellin Landri, Clémence Marin, Mourad Hamimed, Laurent Arnaud, Melanie Karlsen, Kevin Atsou, Sivan Bokobza, Pauline Fleury, Arnaud Boyer, Clarisse Audigier-Valette, Stéphanie Martinez, Hervé Pegliasco, Patrice Ray, Lionel Falchero, Antoine Serre, Nicolas Cloarec, Louisiane Lebas, Stephane Hominal, Patricia Barre, Sarah Zahi, Ahmed Frikha, Pierre Bory, Maryannick Le Ray, Lilian Laborde, Virginie Martin, Richard Malkoun, Marie Roumieux, Julien Mazieres, Maurice Perol, Eric Vivier, Sebastien Benzekry, Jacques Fieschi, Fabrice Barlesi. Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB120.

Abstract LB120: Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial

Eric Vivier

Papers

Cellular aspects of lymphoid differentiation: T and NK cells

Les cellules NK

The Novel Trifunctional Anti-BCMA NK Cell Engager SAR'514 Has Potent in-Vitro and in-Vivo Anti-Myeloma Effect through Dual NK Cell Engagement

B7h6 -bindende monoklonale antikörper und ihre verwendung

Abstract LB120: Comprehensive biomarkers analysis to explain resistances to PD1-L1 ICIs: The precision immuno-oncology for advanced non-small cell lung cancer (PIONeeR) trial