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Immune System and Cancer J.club 07/29/03. What are NK cells? A part of the native immune system, share a common early progenitor with T cells but do.

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Presentation on theme: "Immune System and Cancer J.club 07/29/03. What are NK cells? A part of the native immune system, share a common early progenitor with T cells but do."— Presentation transcript:

1 Immune System and Cancer J.club 07/29/03

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3 What are NK cells? A part of the native immune system, share a common early progenitor with T cells but do not develop in the thymus ~ 10% of blood lymphocytes, defined by surface markers (ex. CD56, NK 1.1, CD2, CD16) Activated by IFN , IFN  and IL-12 (IL-12 commonly used to activate NK cells in vitro) Involved in early response to infection with certain viruses and intracellular bacteria (first line of defense, giving CTLs time to differentiate)

4 “Natural Killers” NK discovered as tumor killer cells: Mice were immunized against a tumor, then their lymphocytes tested for ability to kill tumor cells in vitro. But negative controls – lymphocytes from unimmunized mice or mice Immunized against a different tumor – also killed tumor cells very well! NK assay: 51 Cr release from YAC-1 cells

5 MHC/HLA review

6 KIR CD94 +a/b +c, e/h, f NKG2d NCR NK receptor overview

7 NK receptors Most inhibitory receptors recognize MHC I molecules 2 groups: Killer Immunoglobulin Receptors (KIRs) C-type lectin receptors (CD94+NKG2 family member) Both have activating counterparts, but inhibitory signals dominant. Activation/inhibition depends on: KIRs - long cytoplasmic tail with ITIMs vs. short tails + adaptor with ITAMs C-type lectin receptors - NKG2 member: a/b activating, c, e/h, f inhibitory

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9 NKG2d human and mouse ligands RAE-1/H60 evidence: Tumors expressing RAE-1 or H60 are rejected, NK cell-dependent. Mice immune to re-challenge with the same tumor cells, even if RAE-1/H60 are no longer expressed – a role for adaptive immune system

10 New activating receptor: NKG2d Low homology to other NKG2 receptors, an activating receptor conserved between humans, mice and rats Expressed on NK cells, macrophages,  /  and  /  CTL’s Homodimer, forms an activating complex with DAP-10, which contains SH2 domains and recruits PI3K Can override inhibitory signals from KIRs and C-type lectins

11 Killing pathways (from Takeda et al, 2002)

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14 Adhesion molecules may help NK get to tissue Human and rat NK cells synthesize fibronectin, mAb’s against FN block NK cytotoxicity against YAC-1 NK cells express  4  1 and  5  1 integrins, mediate adhesion to FN in an in vitro assay NK cells express L-selectin, its expression is upregulated by IFN , IL-10 and IL-12 IL-12 also promotes NK adhesion to P and E (endothelial) selectins under flow conditions LFA-1 N-CAM

15 Immune surveillance idea and NK cells In 1909, Paul Ehrlich proposed that the immune system could repress carcinomas. Idea was extended in 1957 by Burnet/Thomas – “immune surveillance” as a way of maintaining tissue homeostasis. NK cells a good candidate: Many virally infected and tumor cells express less MHC I, escape CTL detection/killing NK cells kill MHC I – cells in vitro NK reject MHC I – tumor cells, not same cells MHC I + (same experiment for mets.) Irradiated mice get MHC I – lymphocytes, rapid NK-mediated disappearance Atomic bomb/ Chernobyl survivors have mutations in many different genes, except HLA loss in T cells

16 Tumor/NK evidence in mice Direct: NK cells kill MHC I - tumor cells in vitro Eliminate tumor cells from circulation of mice/rats Protect mice from MCA skin carcinogenesis CTL knockouts have OK control of carcinogen-induced sarcoma growth, perforin knockouts (no CTL or NK activity) have deficient control Correlative: A/J mice have low NK activity and high rate of lymphoma, C57/BL6 mice have high NK cell activity and low rate of lymphoma Mice selected for low acute inflammatory response (AIR) are more susceptible to skin carcinogenesis by DMBA/TPA, and have more lung metastases than wt. or mice selected for high AIR

17 Tumor/NK evidence in mice Drawbacks: No good data on protection from spontaneous tumors (except MCA) Good stimulation by blood cells but few other (ex. Not by low MHC I liver) In vitro models often activated by cytokines at far above physiological levels NK cells require homing signals (MIP-1  for homing to CMV foci in liver) No good mouse model lacking NK cells (until very recently: a group was using a granzyme A promoter to express Ly49A cDNA, and got a mouse that’s specifically NK-deficient, both by FACS and by functional assays The mouse has impaired control of tumor growth/mets., confirmed NK role by adaptive transfer)

18 Tumor/NK evidence in people Direct: In vitro, IL-12 activated human NK cells are capable of killing MHC - tumor cells Chediak-Higashi syndrome – impaired NK degranulation, susceptible to highly metastatic lymphomas Correlative in vivo: Patients on immunosuppressants get more blood tumors People with congenital or acquired immunodeficiencies have a significantly higher incidence of malignancies (viral infection?) NK is impaired in cancer patients, by in vitro studies on YAC-1 and IFN response High peripheral blood NK activity (in treated, apparently disease-free patients) correlates with longer metastasis-free survival

19 NKT cells A recently discovered subpopulation of  T cells that express NK markers (ex. NK 1.1, Ly49 in mice), CD44, Ly6C Originate in bone marrow, differentiate in the thymus Express a limited set of T cell receptors, CD4 + /DN (60%/40%) CD1-dependent activation (MHC I – like proteins conserved in mammals) Implicated in immunoregulation and tumor growth, although not clear if alone or NK-regulated

20 CD1 ligand details Sites of constitutive expression in mouse: thymus, liver, spleen, lung NKT recognize CD1 bound to glycolipid (experimentally used -  -galactosylceramide,  -GalCer)

21 NKT function Specialized regulatory component of immune system? Secrete large amounts of Th1 and Th2 cytokines upon stimulation, fast Th1 – inflammatory, IFN  main cytokine, involves CTLs and macrophages Th2 – humoral, IL-4 main cytokine, stimulates T-helper cells and Ab production Can rapidly stimulate T and B cells in antigen-nonspecific manner Activate NK cells, macrophages, recruit dendritic cells Can induce Fas-mediated killing of CD1 + thymocytes Experimentally activated by anti-CD3

22 NKT evidence in cancer Rag -/- mice (lack NKT, T and B cells) get more metastases than wt mice with low IL-12 stimulation. Corrected by adoptive transfer of NKT cells.  -GalCer is beneficial in preventing tumor growth/mets. in mice (stimulation of dendritic cells to release IL-12 and activate NK?) IFN  release also important (stimulate TRAIL expression on NK?) Important in resistance to MCA-induced fibrosarcomas (no exogenous  -GalCer or IL-12 stimulation) Purified NKTs cytotoxic to syngeneic MCA-induced tumor line

23 NK/NKT big picture:

24 Innate Immune Responses -- components: Macrophage, Dendritic cells, Neutrophils, Mast cells, Eosinophils, Basophils NK cells, NKT cells Complement system Immune System

25 Acquired Immune Responses B cells CD4 + T cells CD8 + T cells

26 Cancer Immunosurveillance Hypothesis “It is an evolutionary necessity that there should be some mechanism for eliminating or inactivating such potentially dangerous mutant cells and it is postulated that this mechanism is of immunological character” -- Macfarlane Burnet and Lewis Thomos (1957) Data disfavored the hypothesis: studies using nude mice 1) Osias Stutman used CBA/H background, look atMCA carcinogen-induced tumor wt/nudenu/nu 7/39, 95days5/27, 90days 2)10,800nu/nu ~ wt mice in spontaneous tumor develp.

27 Cancer Immunosurveillance Hypothesis Data supporting the hypothesis INF-γ data: block, KO, DN IFNGR1,or STAT-1 KO mice have more spon. Or induced tumors ; Perforin-/- more prone to MCA-tumor Rag2-/- increased rate of spontaneous tumor in aged mice Other KO mice researches

28 Cancer Immunosurveillance Hypothesis Correlative data supporting the hypothesis: Immune-suppressed patients have higher incidence of melanoma, lung cancer; Positive correlation between tumor infiltrating lymphocyte response and increased survival (melanoma, breast, colon, prostate…)

29 Cancer Immunoediting

30 Acquired Immune System? Not enough! CD8-/- mice seems to have similar rate of MCA induced tumor to WT; (low MHC I!!) CD4-/- mice can reject syngeneic tumor graft while CD8-/- can’t; Rag2-/- In PND patients, CTLs targeting neuornal antigen cdr2 seem to protect the patients from tumor growth.

31 Innate Immune Responses and Cancer --- Inflammation and Cancer Again, the hypothesis that “tumor: wounds that fail to heal” is around for a long time. Virchow hypothesized that the origin of cancer was at sites of chronic inflammation. –1863 But, is it true? Is inflammation helping or hindering tumor growth?

32 Innate Immune Responses and Cancer --- Inflammation and Cancer Again, like everything else, two opposite views: 1) Inflammatory infiltrations contribute to tumor growth by inducing DNA damage, providing growth and surviving factors, angiogenic/ lymphangiogenic factor, and proteases; -- “Foes” 2) Inflammatory infiltrations help to kill transformed cells, therefore limiting the growth of tumor. – “Friends”

33 Innate Immune Responses and Cancer --- Inflammation and Cancer Coussens LM and Werb Z, Nature, 2002, 420:860 Balkwill F and Mantovani A, Lancet, 2001, 357:539 Data supporting “Foes” 1) Association between chronic inflammation and cancer risk MalignancyInflammatory stimulus Bladderschistosomiasis Cervical papillomavirus Colorectalinflammatory bowel disease Pancreaticchronic pancreatitis Lungbronchitis etc…

34 Inflammation and Cancer Cellular components Polymorphonucleates (PMNs) MMPs ECM remodeling, Facilitate migration Chemokines (IL- 8, IP-10, MIG, MIP-1a,b etc) Recruit TAMs VEFG Angiogenesis Mast cells TFN-a, VEGF, FGF-2, IL-8 Angiogenesis Tryptase Chymase

35 IL-2 IFN-g IL-12 Kill tumor cells CTLs IL-10 (tumor as well) TGF-b1 PDG bFGF TGF-a IGF-I/II Tumor growth TNF-a IL-1 Thrombospondin-1 Angiogenesis MMPs, uPA ECM remodeling, Facilitate migration Macrophages (TAMs)

36 Inflammation and Cancer Data supporting “Friends” 1)Individual cytokines been shown to mediate tumoricidal activity (TRAIL); 2)Activated macrophages mediate tumor rejection; 3)Some report says TAM positively correlate disease-free probability after surgery (while others report not informative, both prostate cancer);

37 Why all these conflicting data? They are looking at different stages; Csf1 op /csf1 op (do not express CSF1 which recruits MAPs): does not affect the incidence or the growth of the primary tumors, but delayed the dev. to invasive, metastatic carcinomas.  2 stages: CSF-1 promote the later stage. - Lin EY et al., 2001

38 Why all these conflicting data? Depend on the type of tumor and the stage of tumor– secrete cytokines, chemokines to attract leukocytes,actively involved in the modulation of immune responses (Th1 vs. Th2 etc..)


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