el sistema inmunolÓgico en el desarrollo de la … · the human immune system: basics adaptive:...
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Dra Ana Arance
Servicio de Oncología Médica
Hospital Clínic Barcelona
EL SISTEMA INMUNOLÓGICO
EN EL DESARROLLO DE LA
ENFERMEDAD NEOPLÁSICA
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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
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Hallmarks of cancer
Hanahan and Weinberg, Cell 2011
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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
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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
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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
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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
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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
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• 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
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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
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Cancer Immunoediting
Tumors in immunocompetent mice are qualitatively different from tumors in
immunodeficient mice.
Schreiber et al. Science 2011
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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
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Dunn, Nature Immunology, 2002
Immunity & Cancer: Immunoediting
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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
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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
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Inmunoediting: TILs
Pages et al. NEJM 2005; Curiel et al. Nat Med 2004
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The immune contexture in human
tumours
Fridman et al. Nature 2012, 12:298
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Pages et al. JCO 2009;Mlecknik et al. JCO 2011; Erdag et al. Cancer Res 2012
Immune Score
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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;
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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
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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
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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
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• 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
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MUCHAS GRACIAS