Pierre Busson (Gustave Roussy, France)
“Galectin-9 and Other Factors of Immune Escape in NPC Tumor Microenvironment: How to Bring Them Under Control?”
- Overview of TME
- [Co-evolution of tumor and stroma]M. Here’s at al, J Pathol 2013 (squamous-columnar junction cells
- From tumor micro environment to tumor macro-environment
- A gradient from tumor interstitial to the bloodstream
- Distant site: increase of Treg, NK and downregulation of CD4
- Normal-tumor heterogeneity of the malignant cells
- Nortmoxiac vs hypnosis or necrotic
- EBV latent vs EBV lytic
- LMP10positive vs LMP1 negative
# Diversity of the Trojan cells
• non-leukocytes:
• Fibroblasts
• Endotheli
[Immune escape in NPC]
• first paradox: immune escape min the context of a hot tumor
(immune rejection. + immune tolerance)
*second paradox: the abundance of T-rugs inside the tumor seems to to be predictive of a good prognosis.
*Third paradox: malignant NPC cells are equipped fo interactions with effector T-cell`
*
C15, C17 PDX immune profiles
Observationss on NOC PDXs.Agathangellou et al Am I Pathol 1995
Extra-cellular factors of immune tolerance in NPCs
– Cytokines
–viral parodists (vIL10, BARF1, soluble BZLF1, LMP1 positive exonerates)
– host factors (galectin , IDO cancer letter 2010)
Exocets from malignant NPC cells as agents of immune tolerance. (Dunkers et al J Immunol 2000)
Jiang-Li’s team (Sysucc) plasma tumor
Exocets containing Class II, gelatin , membrane-bound TGFb. Oncotarget 2015,
NPC cytokines as agents of immune tolerance. Change et al CCR 2008, Lin et al JCI 2013, LIF and CCL20 (MIP3a), Muzak et al JNCI 2015 (involves CCL20, IL1 and LIF? He mentioned “Taiwan”??)
Inflamsomsome (IL1A,
Galectin-9 structural characteristics and resultation
Low expression of gal-9 in most healthy tissues
Up-regulation in inflammatory conditions
Extra-cellular galectin-9
Immuno-suppressive effectors of extra-cellular gal-9
• overall gal-0m is immuno-suppressive in virtually all experimental murine systems
• Pro-inflammatory and immunotherapy-suppressive effects on various cell types
• Multiple surface receptor is: Tim-3 CD44, Dectine 1, CD206
The status if galectin-9 in NPCs
Consistently expressed in NPC cells extreametly abundant in tuomor sections,
Extra-cellular gal-9 in other human malignancies
^^ Aims of current basic and translational studies on gal-9
1. Exploring gal-9 effects on human T-cells not involving Tim-3 (apoptosis is independent of calcium mobilization induced by Gal-9
2. Calcium mobilization by Gal-9 requires an intact TCR complex
3. Next step: exploration
4. Building a syngenic tumor model with and w/o gal-9
5. Towards gal-9 neutralization : isotonic CT26 cells W/Wo gal (for balb C-mic, production of anti-gel-9 neutralizing antibodies. (H-immune therapeutics). Antibodies Orissa-reacting with murine gal-9 Gal-Nab 1 and 2 ==> this antibody can prevent the apoptosis of peripheral CD4+T in vitro and In vivo assessment of antibodies neutralizing gal-9.: possible stromatolites galectin -9 from stromal is a issue, thus next step is to combine with anti-PD1)
Using antibodies blocking Lag3 might be an option
IL1 CCL20 and LIF are targets of immune evasions
% Kennedy asked: relation between LMP1 and gal-9
% KW asked whether NFKB, PI3K or signaling involved in gal-9 unregulation
Answer: IFNa and IFNG are involved in gal-9 upregulation
Leader asked: checkpoint inhibitor and gal-9 —> cautious about cell line finding (eg LMP1 increase PD1)