Respuesta inmune anti-tumoral. Aura Muntasell Institut Hospital del Mar d Investigacions Mèdiques Parc de Recerca Biomèdica de Barcelona

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1 Respuesta inmune anti-tumoral Aura Muntasell Institut Hospital del Mar d Investigacions Mèdiques Parc de Recerca Biomèdica de Barcelona

2 CANCER IMMUNOEDITING Zitvogel et al Nat Rev Immunol (2006)

3 Evidences for cancer immunoediting in animal models of cancer Spontaneous tumor development in immunodeficient mice B cell Cytotoxicity IFNγ Abs: complement, phagocytosis, ADCC 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 β2 microglobulin-/- (lack cytotoxic pathways and MHC class I): Spontenous development of early-onset B cell lymphomas (sensitive to NK and γδ T cells in wt mice)

4 Evidences for cancer immunoediting in humans 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 malignancy Immunosuppressed transplant recipients: fold increase of developing lymphomas and a range of solid tumors Primary 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)

5 Anti-tumor immune effector cells and mechanisms Innate Immune response Adaptive Immune response Cell cytotoxicity IFNγ and TNFα Phagocytic cells ROS and NO TNFα, IL-6, IL-12 Antigen presentation Phagocytic cells Migration Ag presentation Costimulation Type I IFN, IL-6, IL-12 Cell cytotoxicity IFNγ and TNFα Cytokine IFNγ and TNFα

6 Myeloid cells: from tumor-suppressing to tumor-promoting cells Antigen presentation to T cells T cell and NK cell anti-tumor responses Anthracyclines Oxaliplatin Anti-EGFR mab Cyclophosphamide Irradiation Bortezomid Immunogenic tumor cell death Release of tumor-associated Ags + DAMPs Non-immunogenic tumor cell death Release of tumor associated antigens Anti-tumor Pro-tumor HLA and co-stimulatory molecules Pro-inflammatory Mφ Dendritic cells (mature) Alt. Activated Mφ Tolerogenic DC TAM MDSC T reg CTL and NK cell anergy Pro-neoangiogenesis Matrix remodelling and metastasis

7 Recognition of altered self by NK cells ACTIVATING CD16 NKp30 NKp44 NKp46 NKG2D 2B4 NTBA INHIBITORY KIR2DL (HLA-C) KIR3DL (HLA-B) CD94/NKG2A (HLA-E) ILT2 (LIR-1, CD85j) (HLA-G) IRP60 LAIR HLA Class I MICA, MICB, ULBP 1-6 Activation of NK cell effector functions INDUCIBLE CO-RECEPTORS: CD137, PD-1, CEACAM-1

8 Clinical evidences for NK-cell anti-tumor responses A) HSCT : Elimination of minimal residual disease (GvL) Allo-HCT Haploidentical allo-hct Alloreactivedonor NK-cell infusions Probability of relapse Curti A, Clin Canc Res., 2016 B) Tumor AntigenspecificmAb-basedtherapies (IgG1): Rituximab Alemtuzumab Trastuzumab BT474 Clynes RA, Nat Med., 2000

9 T cell antigen recognition and activation T cell Receptor Repertoire Two signal model Unique specificity determined by the TCR TCR: heterodimer (αβ or γδ) Generated by somatic recombination of TCR gene fragments along T cell maturation Selection processes to ensure tolerance B7 CD28 Naïve T cell repertoire ~10 15 Chen L, Nat Rev Immunol, 2013

10 Phases of T cell response HLA class II HLA class I Cytokine environment

11 Polarization of T cell responses by soluble factors (cytokines) Pro-tumor Anti-tumor

12 Cellular mechanisms for tumor elimination: T cells Tumor Associated Antigens (TAA) Tumor specific mutant Antigens (TSMA) Transformation-independent mutations (i.e. carcinogen- or UV-induced) Mutations in oncogens: p21 ras, p53, translocations (bcr/abl) Onco-fetal Antigens: CEA and AFP Overexpressed genes: HER-2 Genes with restricted tissue expression: MAGE Diferentiation molecules: CD20, MART-1 Post-translational modifications: MUC1 Viral associated antigens: Papilomavirus (E6,E7) Virus de Epstein Barr (EBNA )

13 Modulation of T cell effectors by inducible co-receptors Co-stimulatory: TNF receptor subfamily Inhibitory co-receptors Chen L, Nat Rev Immunol, 2013

14 CANCER IMMUNOEDITING Zitvogel et al Nat Rev Immunol (2006) 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

15 CANCER IMMUNOEDITING by IMMUNE CELLS Aptsiauri N, SpringerBriefs in Cancer Research, 2013

16 Cancer Immunoediting Zitvogel et al Nat Rev Immunol (2006)

17 Tumor immune escape mechanisms Tumor variants. A) AVOID B) RESIST Immunological Ignorance: encapsulated tumors, fibroblasts, ECM, low antigen load, alterations in HLA expression/antigen presentation Mutations in death-inducing receptors (i.e. Fas, TrailR) Overexpression of anti-apoptotic molecules (i.e. FLIP, BcL-X) C) SUPPRESS Induction of tolerance to tumor antigens Suppression of cytotoxic lymphocyte infiltrate ACTIVE.anti-tumor immune responses

18 Tumor immuno suppressor mechanisms Secretion of immunosuppressive Soluble factors: - TGFβ - VEGF - IL-10 - smica - sfasl TUMOR CELL Expression of T/NK-cell inhibitory molecules - B7-H1 - HLA-G/HLA-E - PD1-L IMMUNE CELLS Differentiation to CD4+CD25+Foxp3+ T reg Immunossuppresive myeloid cell populations CTL apoptosis Inhibition of CTL proliferation Loss of signal transduction molecules (i.e. CD3ζ) T cell functional exhaustion (PD-1, CTLA-4, LAG 3) Poor innate cell activation IDO + DC

19 Tumor microenvironment and T cell exhaustion The immunossupressive nature of tumor microenvironment (hypoxia, TGFβ, T regs) often renders the infiltrated T cells dysfuntional (exhausted). Gradual process PD-1 TIM3 CTLA4 BTLA CD160 LAG3 2B4 Freeman, JEM, 2006 Gradual, dynamic and reversible process

20 Immune Dysregulation within the Tumor microenvironment Innate Immune response Adaptive Immune response MDSC M2 macrophage Regulatory DC Secretion of NO Arginase Cys sequestration IL10, TGFβ VEGF MMPs IDO expression Tolerogenic Signals Defective antigen presentation Functional exhaustion IL-10, TGFβ (Sink for IL-2) Impaired CTL activation

21 Cancer Immunoediting Zitvogel et al Nat Rev Immunol (2006)

22 Switching to anti-tumor effectors with Immunotherapy Innate Immune response Adaptive Immune response IFNα IL-12 IL-15 Anti-KIR Anti-PD1 Anti-CSF-1R Poly I:C BCG Vaccines IDO inhibitors Anti-PD1 Anti-CTL4 Anti-CTL4 (IgG1) unlicensed NK cell MDSC M2 macrophage Regulatory DC CTL Regulatory T cell

23 Final thoughts 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 The natural history of the individual tumor and the oncogenic changes that it has acquired will condition suitable immunotherapeutic approaches Immunotherapy will work best in combination, as tumor cells upregulate multiple immunocheckpoint pathways to evade the immune response There is a need for identifying immune system related 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

24 Thank you for your attention