Respuesta inmune anti-tumoral

Aura MuntasellInstitut Hospital del Mar dInvestigacions Mdiques

Parc de Recerca Biomdica de Barcelona

Zitvogel et al Nat Rev Immunol (2006)

CANCER IMMUNOEDITING

Evidences for cancer immunoediting in animal models of cancerSpontaneous tumor development in immunodeficient mice

B cell

A) RAG2-/- (Lacks B and T cells): Develop spontaneous adenocarcinomes of the intestine and lung

B) RAG2-/- STAT1-/- (Lacks B and T cells, deficient in type I and II IFN signaling): Increased spontaneous tumor incidence with broad tumor spectrum: adenocarcinomes of the intestine and lung, breast, colon.

C) Perforin -/- (lacking cytotoxic pathways):Spontenous development of late-onset B cell lymphomas (sensitive to CD8 T cells in wt mice)

D) Perforin-/- and 2 microglobulin-/- (lack cytotoxic pathways and MHC class I): Spontenous development of early-onset B cell lymphomas (sensitive to NK and T cells in wt mice)

Cytotoxicity IFN Abs: complement, phagocytosis, ADCC

A) Spontaneous tumor regression: Certain tumors regress spontaneously suggesting an immunological response (i.e. melanomas). Spontaneous regressing melanoma lessions are accompanied by clonal expansion of specific T cells

B) Immunosuppressed patients: is associated with a higher risk of malignancyImmunosuppressed transplant recipients: 3-100 fold increase of developing lymphomas and a range of solid tumorsPrimary and acquired immunodeficiencies: increased incidence of lymphomas and tumors of viral etiology

C) Tumor immune infiltrate: Tumors with severe mononuclear cell infiltatre (CD8, Th1) have a better prognosis than those lacking it (i.e. microsatellite unstable colorectal tumors, MSI)

D) Paraneoplastic neurological disorders (PNDs) arise as a consequence of antibody and T cell responses against certain autologous tumors that ectopically express proteins whose expression is normally restricted to the nervous system

E) Immunotherapy with checkpoint inhibitors: clinical beneffit particularrly in immunogenic tumors (i.e. melanoma)

Evidences for cancer immunoediting in humans

Anti-tumor immune effector cells and mechanisms

Innate Immune response Adaptive Immune response

Cell cytotoxicityIFN and TNF

Phagocytic cellsROS and NOTNF, IL-6, IL-12Antigen presentation

Phagocytic cellsMigrationAg presentationCostimulationType I IFN, IL-6, IL-12

Cell cytotoxicityIFN and TNF

Cytokine IFN and TNF

Antigen presentation to T cellsT cell and NK cell anti-tumor responses

T regCTL and NK cell anergyPro-neoangiogenesisMatrix remodelling and metastasis

Myeloid cells: from tumor-suppressing to tumor-promoting cells

Non-immunogenic tumor cell deathRelease of tumor associated antigens

Immunogenic tumor cell deathRelease of tumor-associated Ags

+ DAMPs

AnthracyclinesOxaliplatinAnti-EGFR mAbCyclophosphamideIrradiationBortezomid

Pro-inflammatory MDendritic cells (mature)

Alt. Activated MTolerogenic DCTAMMDSC

HLA and co-stimulatory molecules

Anti-tumor

Pro-tumor

Activation of NK cell effector functions

ACTIVATING INHIBITORY

KIR2DL (HLA-C)KIR3DL (HLA-B)CD94/NKG2A (HLA-E)ILT2 (LIR-1, CD85j) (HLA-G)IRP60LAIR

CD16NKp30NKp44NKp46NKG2D2B4NTBA

INDUCIBLE CO-RECEPTORS: CD137, PD-1, CEACAM-1

Recognition of altered self by NK cells

HLA Class I

MICA, MICB, ULBP 1-6

Clinical evidences for NK-cell anti-tumor responses

A) HSCT : Elimination of minimal residual disease (GvL)

Allo-HCT

Haploidentical allo-HCT

Alloreactive donor NK-cell infusions

B) Tumor Antigen specific mAb-based therapies (IgG1):

Rituximab

Alemtuzumab

Trastuzumab

Clynes RA, Nat Med., 2000

BT47

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Curti A, Clin Canc Res., 2016

T cell antigen recognition and activation

Unique specificity determined by the TCR

TCR: heterodimer ( or )

Generated by somatic recombination of TCR gene fragments along T cell maturation

Selection processes to ensure tolerance

Nave T cell repertoire ~1015

T cell Receptor Repertoire

Chen L, Nat Rev Immunol, 2013

Two signal model

CD28B7

Phases of T cell response

Cytokine environment

HLA class II

HLA class I

Polarization of T cell responses by soluble factors (cytokines)

Anti-tumorPro-tumor

Viral associated antigens:Papilomavirus (E6,E7)Virus de Epstein Barr (EBNA )

Onco-fetal Antigens: CEA and AFPOverexpressed genes: HER-2Genes with restricted tissue expression: MAGEDiferentiation molecules: CD20, MART-1Post-translational modifications: MUC1

Transformation-independent mutations (i.e. carcinogen- or UV-induced)Mutations in oncogens: p21ras, p53, translocations (bcr/abl)

Cellular mechanisms for tumor elimination: T cellsTumor Associated Antigens (TAA)

Tumor specific mutant Antigens (TSMA)

Modulation of T cell effectors by inducible co-receptors

Co-stimulatory: TNF receptor subfamily

Inhibitory co-receptors

Chen L, Nat Rev Immunol, 2013

Zitvogel et al Nat Rev Immunol (2006)

CANCER IMMUNOEDITING

Elimination of tumor cells with strong mutant antigens Spare tumor cells with weaker antigens Promote epigenetic silencing of tumor-specific antigens/HLA-I Selection of tumor variants that scape from IS

CANCER IMMUNOEDITING by IMMUNE CELLS

Aptsiauri N, SpringerBriefs in Cancer Research, 2013

Zitvogel et al Nat Rev Immunol (2006)

Cancer Immunoediting

Tumor immune escape mechanisms

Tumor variants.

A) AVOID

B) RESIST

C) SUPPRESS

.anti-tumor immune responses

Immunological Ignorance: encapsulated tumors, fibroblasts, ECM, low antigen load, alterations in HLA expression/antigenpresentation

Mutations in death-inducing receptors (i.e. Fas, TrailR)

Overexpression of anti-apoptotic molecules (i.e. FLIP, BcL-X)

Induction of tolerance to tumor antigens

Suppression of cytotoxic lymphocyte infiltrate

ACTIVE

Tumor immuno suppressor mechanisms

TUMOR CELL

IMMUNE CELLS

Expression of T/NK-cell inhibitory molecules

- B7-H1- HLA-G/HLA-E- PD1-L

Secretion of immunosuppressiveSoluble factors:

- TGF- VEGF- IL-10- sMICA- sFasL

Differentiation to CD4+CD25+Foxp3+ T reg

Immunossuppresive myeloid cell populations

Poor innate cell activation IDO+ DC

CTL apoptosisInhibition of CTL proliferationLoss of signal transduction molecules (i.e. CD3)T cell functional exhaustion (PD-1, CTLA-4, LAG 3)

Gradual process

Tumor microenvironment and T cell exhaustion

The immunossupressive nature of tumor microenvironment (hypoxia, TGF, T regs) oftenrenders the infiltrated T cells dysfuntional (exhausted).

Freeman, JEM, 2006

PD-1

TIM3CTLA4BTLACD160LAG32B4

Gradual , dynamic and reversible process

Immune Dysregulation within the Tumor microenvironment

Innate Immune response Adaptive Immune response

Secretion of NOArginaseCys sequestration

IL10, TGFVEGFMMPs

IDO expressionTolerogenic SignalsDefective antigenpresentation

Functional exhaustion

IL-10, TGF(Sink for IL-2)Impaired CTL activation

MDSC M2 macrophage Regulatory DC

Zitvogel et al Nat Rev Immunol (2006)

Cancer Immunoediting

IDO inhibitors

Switching to anti-tumor effectors with Immunotherapy

Innate Immune response Adaptive Immune response

MDSC M2 macrophage Regulatory DCCTL Regulatory T cell

unlicensedNK cell

IFNIL-12IL-15

Anti-KIRAnti-PD1

Anti-CSF-1R

Anti-PD1Anti-CTL4

Poly I:CBCGVaccines

Anti-CTL4 (IgG1)

Final thoughts

The natural history of the individual tumor and the oncogenic changes that it has acquired will condition suitable immunotherapeutic approaches

Immune system has several effector cells with the potential for eliminating tumors. Those effector cells and mechanisms involved in tumor elimination differ among tumors depending on their:

- nature- immunogeneicity- accessibility

There is a need for identifying immune systemrelated biomarkers allowing to categorize patients - optimizing the selection of candidates with high response phenotypes. - facilitate decisions on the convenience of testing co-adjuvant/combination therapies in a personalized manner

Immunotherapy will work best in combination, as tumor cells upregulate multiple immunocheckpoint pathways to evade the immune response

Thank you for your attention

Nmero de diapositiva 1Nmero de diapositiva 2Nmero de diapositiva 3Nmero de diapositiva 4Anti-tumor immune effector cells and mechanismsNmero de diapositiva 6Nmero de diapositiva 7Nmero de diapositiva 8T cell antigen recognition and activationPhases of T cell responseNmero de diapositiva 11Nmero de diapositiva 12Nmero de diapositiva 13Nmero de diapositiva 14Nmero de diapositiva 15Nmero de diapositiva 16Nmero de diapositiva 17Nmero de diapositiva 18Nmero de diapositiva 19Immune Dysregulation within the Tumor microenvironmentNmero de diapositiva 21Nmero de diapositiva 22Nmero de diapositiva 23Nmero de diapositiva 24