Download EL SISTEMA INMUNOLÓGICO EN EL DESARROLLO DE LA

EL SISTEMA INMUNOLÓGICO
EN EL DESARROLLO DE LA
ENFERMEDAD NEOPLÁSICA
Dra Ana Arance
Servicio de Oncología Médica
Hospital Clínic Barcelona
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)
Ribas et al. JCO 2003
* 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
Adaptive immune system
TH 1 citotoxicity --- CTL
CHM-péptido II
TH 2 humoral response --- L B
CD4
TH 17 inflammation
TReg immune suppression
Ag
CD8
CHM-péptido I
Célula dendrítica
CTL
Palucka et al. Nat Rev Cancer 2012
Generation and regulation of antitumor immunity
CAPTURE & PRESENTATION
Presentation (MHC class II)
+/Maturation
Stimulus
T cell co-stimulatory molecules
Cross-presentation (MHC class I)
RESPONSE
PROTECTIVE T CELL
CD28 (OX40) – CD80/86 (OX40L)
Increase effector T cells
RESPONSE
TOLERANCE
CTLA4 – CD80/86
PD1 – PDL1/PDL2
Increase of Regulatory T cells
IMMUNOSUPPRESSION
BARRIER
PDL1/PDL2
VEGF
PGE2
Arginase
IDO
Mellman et al. Nature 2011; Palucka et al. Nat Rev 2012
Cancer immunosurveillance
• Regresiones tumorales espontáneas
• Síndromes paraneoplásicos
• Desarrollo de vitíligo
• Detección de Ac y linfocitos T activados en pacientes con cáncer
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
- 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
Dunn, Nature Immunology, 2002
Inmunoediting: TILs
*Incremento de TILs generalmente
asociado buen pronóstico en
tumores sólidos: ovario, melanoma,
colon, mama, pulmón…..
*Subpoblaciones específicas
de TILs y pronóstico
Zhang et al. NEJM 2003; Erdag et al. Cancer Res 2012; Fridman et al Nature 2012
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
Immune Score
Pages et al. JCO 2009;Mlecknik et al. JCO 2011; Erdag et al. Cancer Res 2012
Chemokine mediated migration into target tumor sites
•T cell rich
-↑ CD8+ T cells in tumor
microenviroment
- ↑ T lineage specific markers
1/3
-↑chemokines: CCL2, CCL3, CCL4, CCL5,
CXCL9, CXCL10
-Inflammatory signature
•T cell poor
-↓indicators of inflammation
2/3
-↓chemokines for T cell
recruitment
-↑ angiogenesis associated
factors
Harlin et al. Cancer Res 2009; Ji et al. Cancer immunol Immunother 2011; Ulloa-Montoya et al. J Clin Oncol 2013;
Chemokine mediated migration into target tumor sites II
Various chemokines are associated with generating an
anticancer immune context in many human tumors
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
Endothelial cells
Tumor-derived
mediatos
↓ expression of adhesion
molecules
VEGF
PDL1
TGF
VEGF, FGF, ET1
IL-10
Immune cells
M-CSF
IL-6
T regs (TGF, IL10, IL35)
EGFR-Ras
MDSC (TGF, IL10, ROS
Hipoxia, lactic acid
Dendritic cell
↑IDO
↑PGE2
↓chemokine expression
Motz et al. Immunity 2013
CONCLUSIONS
• 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
MUCHAS GRACIAS