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Dr. Pedro Berraondo
[email protected]
Programa de Inmunología e Inmunoterapia
The immune system must make two decisions:
1) To respond or not?
2) What kind of response do you use?
Immune response is determined by tissue damage.
Matzinger P. Science. 2002. 296(5566):301-5.
• Molecular pattern exposed in danger situation:
hydrophobic zones and nucleic acids
1) Molecular patterns associated with pathogens:
Lipopolysaccharide, peptidoglycan, lipoteicoic acid, Double-stranded and singlestranded RNA, CpG motifs
2) Molecular patterns associated with damage:
EDA, high-mobility group box 1, heat shock proteins, ATP, uric acid,
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Melero, I. et al. Nat. Rev. Clin. Oncol. 2014.
Bezu L et al. 2015 Front Immunol 24; 6:187
Melero, I. et al. Nat. Rev. Clin. Oncol. 2014.
Biggs MJP et al. Interface. 2011.
Kershaw MH et al. Nature Reviews Cancer 2013;13:525-541
Chen DS et al. Nature 2017;541:321-330
Chen L et alNature Reviews Immunology 13, 227-242 (April 2013)
Melero, I. et al. Nat. Rev. Clin. Oncol. 2014.
Intracellular viruses, bacteria and tumors
IFNγ
Grmz
ROS
CTLs
Tissue repair to block large organism
B cells
(IgG2)
Macrophages
(M1)
NK and ILC1s
IL-25
IL-33
TSLP
B cells Macrophages
Eosinophils
(IgG1 or IgGE) (M2)
Extracellular microorganism
ILC2s
IL-1β
IL-23
Neutrophils
ILC3s
Epithelial cells
(AMPs)
Exclusion of microorganism
Myeloid suppresor cells
B cells
(IgA)
Spitzer MH DS et al. Cell 2017;168:1-16
Zitvogel et al. Nature Reviews Immunology 6, 715–727 (October 2006) | doi:10.1038/nri1936
Chen DS et al. Nature 2017;541:321-330
Melero, I. et al. Nat. Rev. Clin. Oncol. 2014.
A) Tumor variants invisible to the immune system
1) Alteration of the antigen-processing machinery
2) Tumor variants with reduced sensitivity to immune effectors
3) Alteration of effector cell trafficking
B) Tumor variants that suppress the antitumor immune response
3) Infiltration of suppressor myeloid cells
4) Infiltration of T regulatory cells
5) Production of immunosuppressive factors
Diminished transport of MHC
I-peptide complexes
Antigen
loss
CTLs
Loss of β2
microglobulin
Loss of
MHC
heavy chain
↓ LMP2/7 ↓ TAP
subunits of
proteasome
Secretory
vesicle
Golgi
ER
Adapted from Drake et al. Adv Immunol. 2006;90:51-81.
Tumor cell
membrane
IFNγ
CTLs
↓ IFNγ
receptor
Tumor
↓ death receptors
↑ decoy receptors
↓ apoptosis:
↓ caspase 8
↑FLIP
Granzyme Bperforin
Adapted from Zitvogel et al. Nat Rev Immunol. 2006 Oct;6(10):715-27.
Motz et al. Immunity. 2013 Jul 25; 39(1): 61–73.
Myeloid derived suppressor cells
T regulatory cells
Dendritic
cell
Tumor
TGF-β
Tumor cell
NK cell
PD-1
IDO
PDL-1
CTLA-4
T lymphocyte
Dendritic
cell
T lymphocyte
Kynurenines
CD-80
o CD-86
Tryptophan
T lymphocyte
Adapted from Berraondo P et al. Medicina Interna Farreras. XVII Edición
Mills KH et al. Nat Rev Immunol. 2004 Nov;4(11):841-55.
Tumor associated
dendritic cells
Myeloid derived
suppressor cells
Tumor associated
macrophages
Gabrilovich DI et al. Nat Rev Immunol. 2009 Mar;9(3):162-74.
Gabrilovich DI et al. Nat Rev Immunol. 2009 Mar;9(3):162-74.
Mantovani A et al. Trends Immunol. 2002 Nov;23(11):549-55.
Tesone AJ et al. Front Immunol. 2013 Dec 10;4:435.
Cytokines, Co-inhibitory molecules and Enzymes
CD4+ T cell
TADC
TAM
NK
Treg
CTLs
Monjazeb AM et al. Front Oncol. 2013 Jul 26;3:197.
MDSC
Löb S et al. Nat Rev Cancer. 2009 Jun;9(6):445-52.
Vasaturo A et al. Front Immunol. 2013 Dec 3;4:417.
Akhurst RJ et al. Nat Rev Drug Discov. 2012 Oct;11(10):790-811.
O`Garra A et al. Nat Rev Immunol. 2007 Jun;7(6):425-8.
Chen DS et al. Nature 2017;541:321-330
Whiteside TL et al. 2016 Clin Cancer Res 22; 1845-1855