Basic mechanisms of Immunotherapy

Transcription

1 Basic mechanisms of Immunotherapy Making it in a simple Lenguage Dr. Ada G. Blidner Ins8tute of Biology and Experimental Medicine, Buenos Aires, Argen8na adablidner@gmail.com

2 Who, Where, When?

3 Innate and Adaptive Immune Response Fast Recognizes Pathogen associated paterns Capable of elimina8ng infec8ons Ready to act, in the 8ssues Interacts with AIR Dranoff, Nature Reviews, 2004 Slow Recognizes specific an8gens Very efficient in elimina8ng infec8ons In the Lymph nodes, needs IIR ac8va8on to migrate to 8ssues and act

4 Antigen presentation and Priming Koichi, Nature Reviews, 2012 Huppa, Nature Reviews, 2003

5 Integrating the Immune Response

6 What are checkpoints good for? PD-1 PD-1 CD4 CTLA-4 BTLA CTLA-4 LAG3 Treg BTLA LAG3 PD-1 CD8 CTLA-4 BTLA HVEM HVEM LAG3 B PD-L1 BTLA LAG3 Immune homeostasis PD-L1 VISTA

7 CTLA-4 Activation Sustained Activation CD4 Immunosuppression CD4 Treg CD8 CD8 CTLA-4 migration CTLA-4 Expression Ligand Competition Deactivation of proliferation signals Antigen presentation inhibition

8 PD-1 PD1 CD4 PD1 CD8 PD1 B PD-L1 PD-L2 PD-1 is expressed following T cel activation PD-L1 is expressed in lymphoid and non-lymphoid tissues. PD-L2 mainly in APCs PD1 Treg PD-L1 PD1 PD-L1 PD-L2 PD1 TFh PD-L1 is expressed on Endothelial cells, which inhibit T cell activity in SLO PD-1 is expressed in Exhausted T cells

9 PD-1 Exhausted T Cell PD-1/PD-L1 interaction inhibits TCR mediated T cell activation and Proliferation

10 T cell ON/OFF Co-stimulatory molecules Co-inhibitory molecules Activation Inflammation Autoimmunity Anergy Homeostasis Cancer

11 How do Tumors take advantage of IC? I.S. wins The I.S. selects resistant clones Tumor wins

12 How do Tumors take advantage of IC? EQUILIBRIUM PHASE PD-1 LAG 3 CD4 PD-1 CD8 CTLA-4 BTLA Treg CTLA-4 PD-1 CTLA-4 PD-L1 PD-L2 IL-1B IL-12 IFN-γ MDSCs GM- CSF PD-L1 PD-L2 IDO HVEM

13 CTLA-4 blockade broadens T cell repertoire

14 Differences between CTLA-4 and PD-1 blockade C D D F E E Fife & Bluestone T-cell tolerance mediated by CTLA-4 and PD-1 Pancreatic Lymph Node Peripheral Tolerance Tissue Specific G Inhibition Pancreas Tissue Specific Inhibition T cell Activation T cell Treg T cell Activated T cell Immune Trafficking Islets (β cells) DC DC CTLA-4 - B7-1/B7-2 PD-1 - PD-L1 B7-1/B7-2 CTLA-4 Inhibition 8 Cell 170, 1 14, September 7, 2017 Ligand Concentration PD-1 Inhibition PD-L1/PD-L2

15 Please cite this article in press as: Thorsson et al., The Immune Landscape of Cancer, Immunity (2018), http Th1/Th17 responses correlate with good prognosis A B A B A CC C Fig B DD D The increase in Th17 correlates with a better progonosis (A) O (B) Figur imm (A) Ov rela (B) Co mor immun relatio with mor ty (C) C with a imm (C) CI immun (D) (D) Ri imm immun disc discov mode mod immun imm neoan neo(r high ashigh app family as a (E) Pre infam valid for (E)eaP with v in va diction for e outcom with Confid strapp dict the ac outc narrow

16 iew Personalized Immunotherapy Can we personalize iare detection? IFN-α rapies that Might Affect the Cancer-Immunity Cycle factors that come into play in the Cancer-Immunity Cycle provide a wide range of potential therapeutic targets. This figure highlights examples of erapies currently under preclinical or clinical evaluation. Key highlights include that vaccines can primarily promote cycle step 2, anti-ctla4 can ote cycle step 3, and anti-pd-l1 or anti-pd-1 antibodies can primarily promote cycle step 7. Although not developed as immunotherapies,, radiation therapy, and targeted therapies can primarily promote cycle step 1, and inhibitors of VEGF can potentially promote T cell infiltration into step 5. Abbreviations are as follows: GM-CSF, granulocyte macrophage colony-stimulating factor; CARs, chimeric antigen receptors.

17 Thanks! Immunopathology Lab, Ins8tute of Biology and Experimental Medicine-CONICET Dr. Gabriel Rabinovich, Senior Inves8gator, Full Professor FCEyN-UBA