Dra Ana Arance

Servicio de Oncología Médica

Hospital Clínic Barcelona

EL SISTEMA INMUNOLÓGICO

EN EL DESARROLLO DE LA

ENFERMEDAD NEOPLÁSICA

Tumor and microenviroment

Tumor microenviroment: a complex network composed by tumor cells but

also by stromal, endothelial, and immune cells

Joyce et al. Nat Rev Cancer 2009

Hallmarks of cancer

Hanahan and Weinberg, Cell 2011

The human immune system: Basics

Innate:

dendritic cells, macrophages,

NK/NKT cells

•Sentinel cells

•Inherent ability to rapidly respond to

tissue injury

•No memory or antigen specificity

Ribas et al. JCO 2003

The human immune system: Basics

Adaptive: CD4 Th1, Th2, Th17, Treg,

CD8 T cells / B cells

-Humoral response mediated by

antibodies / Cellular response mediated

by T lymphocytes (TCR)

-Response depend on recognition

involving polymorphic binding proteins

-Ag presentation by APC through the

MHC to CD4 and CD8 TL

-Long lived memory cells

Ribas et al. JCO 2003

Innate immune system

• Células presentadoras de antígeno (APCs) y células dendríticas (DC)

- Estimulan inmunidad innata activando

células NK y NKT

- DCs principales APCs para estimular linfos T naive, punto de partida inmunidad adquirida

- DCs alta densidad de moléculas MHC de superficie y moléculas coestimuladoras

- DCs alta movilidad y producción de citokinas inmunoestimuladoras

- DCs procesan Ags exógenos vía MHC I para estimular LT CD8 (“cross presentation”) y MHC II para activar LT CD4

- Proceso de presentación antigénica DCs – linfos altamente regulado (sinapsis inmune)

* Células Natural Killer (NK)

- No Rc polimórficos (Acs/TCR)

- Destrucción células no sensibilizadas con alteraciones MHC I

- NKT, presentan TCR pero menos variable que el TCR de linfos T

* Macrófagos:

- “Classically activated” tipo M1

- “Alternatively activated” tipo M2, asimilados a tumor-associated macrophages (TAMs)

* Myeloid-derived suppressor cells (MDSC):

- Inhiben respuesta innata/adquirida

Ribas et al. JCO 2003

Palucka et al. Nat Rev Cancer 2012

CD4

CD8

CHM-péptido II

Ag

Célula dendrítica

CTL

CHM-péptido I

TH 1 citotoxicity --- CTL

TH 2 humoral response --- L B

TH 17 inflammation

TReg immune suppression

Adaptive immune system

CAPTURE & PRESENTATION

Presentation (MHC class II)

Cross-presentation (MHC class I) RESPONSE

PROTECTIVE T CELL

CD28 (OX40) – CD80/86 (OX40L)

Increase effector T cells

IMMUNOSUPPRESSION

BARRIER

PDL1/PDL2

VEGF

PGE2

Arginase

IDO

+/-

Maturation

Stimulus

T cell co-stimulatory molecules

RESPONSE

TOLERANCE

CTLA4 – CD80/86

PD1 – PDL1/PDL2

Increase of Regulatory T cells

Mellman et al. Nature 2011; Palucka et al. Nat Rev 2012

Generation and regulation of antitumor immunity

• Regresiones tumorales espontáneas

• Síndromes paraneoplásicos

• Desarrollo de vitíligo

• Detección de Ac y linfocitos T activados en pacientes con cáncer

Cancer immunosurveillance

Schreiber et al. Science 2011; Ribas et al. JCO 2003

Cancer immunosurveillance

The immune status of mice is a critical determinant of their susceptibility

to tumors induced by chemical carcinogens.

Schreiber et al. Science 2011

Cancer Immunoediting

Tumors in immunocompetent mice are qualitatively different from tumors in

immunodeficient mice.

Schreiber et al. Science 2011

Immunity & Cancer: Immunoediting

Dunn, Nature Immunology, 2002

- Reconocimiento células tumorales por células respuesta innata

- Maduración y migración de DCs y presentación cruzada a linfocitos T

- Generación de linfocitos T específicos de tumor

- “Homing” de linfocitos específicos a tumor primario y erradicación

Dunn, Nature Immunology, 2002

Immunity & Cancer: Immunoediting

Dunn, Nature Immunology, 2002

Immunity & Cancer: Immunoediting

- Secreción de citokinas: TGFβ e IL-10

- Inducción de CTLA-4, PD-1

- Inducción de Tregs, Th2 y MDSC

- Pérdida de expresión antigénica via CHM en

superficie tumoral

Inmunoediting: TILs

*Incremento de TILs generalmente

asociado buen pronóstico en

tumores sólidos: ovario, melanoma,

colon, mama, pulmón…..

Zhang et al. NEJM 2003; Erdag et al. Cancer Res 2012; Fridman et al Nature 2012

*Subpoblaciones específicas

de TILs y pronóstico

Inmunoediting: TILs

Pages et al. NEJM 2005; Curiel et al. Nat Med 2004

The immune contexture in human

tumours

Fridman et al. Nature 2012, 12:298

Pages et al. JCO 2009;Mlecknik et al. JCO 2011; Erdag et al. Cancer Res 2012

Immune Score

Chemokine mediated migration into target tumor sites

•T cell poor

-↓indicators of inflammation

-↓chemokines for T cell

recruitment

-↑ angiogenesis associated

factors

•T cell rich

-↑ CD8+ T cells in tumor

microenviroment

- ↑ T lineage specific markers

-↑chemokines: CCL2, CCL3, CCL4, CCL5,

CXCL9, CXCL10

-Inflammatory signature

1/3

2/3

Harlin et al. Cancer Res 2009; Ji et al. Cancer immunol Immunother 2011; Ulloa-Montoya et al. J Clin Oncol 2013;

Various chemokines are associated with generating an

anticancer immune context in many human tumors

Chemokine mediated migration into target tumor sites II

Mlecnik et al. Gastroenterology 2010

Why CD8+ infiltrated tumors can not be rejected?

Negative regulatory mechanisms:

-PD-L1 (interacts with PD-1)

-IDO (indoleamide-2,3-dioxygenasa)

-arginase 1

-CD4+CD25+FoxP3+ Tregs

-Costimulatory ligands (B7-1 and B7-2)

Gajewski et al. Cancer J 2010

Immune Suppression in the Tumor

Microenvironment

Tumor-derived

mediatos

VEGF

PDL1

TGF

IL-10

M-CSF

IL-6

EGFR-Ras

Hipoxia, lactic acid

Dendritic cell

↑IDO

↑PGE2

↓chemokine expression

Immune cells

T regs (TGF, IL10, IL35)

MDSC (TGF, IL10, ROS

VEGF, FGF, ET1

Endothelial cells

↓ expression of adhesion

molecules

Motz et al. Immunity 2013

• T cells remain potent mediators of antitumor immunity, and tumor

infiltration by T cells is a good prosnostic marker in a number of tumor

types

• The interactions between cancer cells and host immune cells in the

tumor microenviroment create an immunosuppressive network that

promotes tumor growth and protects the tumor from immune attack

• Cancer immunology is gaining a significance importance in the recent

years. Implementation and development of new therapeutic strategies.

Ac antiCTLA4 (Ipilimumab)

Ac antiPD1/antiPDL1

Sipuleucel -T

Vacunas MAGE

Terapia celular adaptada

CONCLUSIONS

MUCHAS GRACIAS