Dr. Pedro Berraondo

pberraondol@unav.es

Programa de Inmunología e Inmunoterapia

Matzinger P. Science. 2002. 296(5566):301-5.

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.

• Molecular pattern exposed in danger situation:

hydrophobic zones and nucleic acids

1) Molecular patterns associated with pathogens:

Lipopolysaccharide, peptidoglycan, lipoteicoic acid, Double-stranded and single-

stranded RNA, CpG motifs

2) Molecular patterns associated with damage:

EDA, high-mobility group box 1, heat shock proteins, ATP, uric acid,

Guy B. Nat Rev Microbiol 2007;5:505-517.

Guy B. Nat Rev Microbiol 2007;5:505-517.

Matzinger P, Kamala T.Nat Rev Immunol. 201111(3):221-30.

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.

CTLs B cells

(IgG2)

Macrophages

(M1)

NK and ILC1s

B cells

(IgG1 or IgGE)

Macrophages

(M2)

Neutrophils

Myeloid suppresor cells B cells

(IgA)

IFNγ

Grmz

ROS

Intracellular viruses, bacteria and tumors

Tissue repair to block large organism

Extracellular microorganism

Exclusion of microorganism

ILC2sEosinophils

IL-25

IL-33

TSLP

IL-1β

IL-23

ILC3s Epithelial cells

(AMPs)

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

Adapted from Drake et al. Adv Immunol. 2006;90:51-81.

CTLs

Tumor cell

membrane

Secretory

vesicle

Golgi

ER

Antigen

loss

↓ LMP2/7

subunits of

proteasome

↓ TAP

Loss of β2

microglobulin

Loss of

MHC

heavy chain

Diminished transport of MHC

I-peptide complexes

Adapted from Zitvogel et al. Nat Rev Immunol. 2006 Oct;6(10):715-27.

CTLs TumorIFNγ

Granzyme B-

perforin

↓ IFNγ

receptor

↓ apoptosis:

↓ caspase 8

↑FLIP

↓ death receptors

↑ decoy receptors

Motz et al. Immunity. 2013 Jul 25; 39(1): 61–73.

Adapted from Berraondo P et al. Medicina Interna Farreras. XVII Edición

Tumor

TGF-β

IDO

T regulatory cellsMyeloid derived suppressor cells

Tryptophan

Kynurenines

PDL-1

PD-1

CTLA-4

CD-80

o CD-86T lymphocyte

T lymphocyte

Dendritic

cell

Tumor cell

T lymphocyte

NK cell

Dendritic

cell

Mills KH et al. Nat Rev Immunol. 2004 Nov;4(11):841-55.

Tumor associated

macrophages

Tumor associated

dendritic cellsMyeloid derived

suppressor cells

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.

Monjazeb AM et al. Front Oncol. 2013 Jul 26;3:197.

CTLs

NK

CD4+ T cell

MDSC

TAM

TADC

Treg

Cytokines, Co-inhibitory molecules and Enzymes

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