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26 Cards in this Set
- Front
- Back
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describe spontaneous remission:
-frequency -mediators |
-Rare!
-usually associated with anti-tumor antibodies and CTLS |
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Describe TILs
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-Tumor Infiltrating Lymphocytes
-present in stromal tissue -bind cancer antigen -ANERGIC -not cytotoxic, do not produce INF-g -suggests cancer environment somehow suppresses activation |
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discuss findings of Burnett and Thomas
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-1957
-found evidence for immunological surveillance -hypothesized existence of lymphoctyes with receptors specifc for Tumor AG -tumor-specific lymphocytes can patrol the periphery and recognize novel tumor antigens and eliminate tumors cells |
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describe cancer in HIV patients
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-Increased Incidence of virally-induced:
EBV B cell lymphoma HSV Kaposi Sarcoma HPV Squamous cell CA -->elimination of T-cell response against viral Ag leads to continuous growth of transformed tumor cells **other common neoplasms (colon, breast, prostate) also increased in longer living HIV pts. |
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transplant-associated EBV lymphomas
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-bone marrow transplants
-donor T cells depleted from donated bone marrow to prevent GVHD -recipient T cells also depleted by ablation -also possible in solid organ transplant (Immunosupp-->no CD8+ response); ending immunosupp or t cell admin curative |
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messing with Mice (RAG KO)
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-tumors induced in RAG-/- (lymphocyte deficient) mouse (with MCA-potent carcinogen) will be rejected in a wild-type mouse; tumor size will be smaller
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more messin with mice-further evidence for immuno surveillance
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-absence of IFN-gR, STAT1, IL-12, perforin, RAG, NK cells-->ALL lead to increase of MCA-induced malignancy
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describe role of IFN-gR in tumor rejection
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-for lymphocytes to reject tumor, IFN-gamma receptors need to be expressed in the tumor cells
-IFN-gR--> increase in MHC machinery & ability to present peptides on MHC class I -INF-gammaR -/- tumors persist even in presence of lymphocytes (no ag presentation) -ectopic expression of IFN-gR on tumors allows lymphocytes to recognize and tumor growth limited |
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Model of Innate Recognition and Initiation of the Adaptive Anti-tumor
Immune Response |
-Tumor cells recognized by innate cells (ex: gamma-delta T
cells, NK cells, NKT cells) and activate them via an unknown signal (‘danger signal’) -Innate cells secrete IFN-g and other cytokines to induce: i. Apoptosis of tumor cells ii. Anti-angiogenic factors to starve the tumor iii. Activation of macrophages and DCs to generate IL-12 leading to a CD4/CD8 response iv. DCs migrate to the lymph node continue to present antigen to other T cells that will then migrate back to the tumor to kill it. -->immunization with tumor cells can induce a protective immune response? -has been shown in mice; however, immunity only to same tumor |
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Shared tumor antigens
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-preferred type for immunization
1. Cancer/testes Antigens: expressed embryologically then shut down in adults; can be re-expressed in cancers 2.Differentiation associated antigens (tissue-specific) Ex: prostate specific antigen 3. Gangliosides Ex: MUC-1 (found in many cancers) **could be used to immunize against many tumor types |
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Unique Tumor Antigens
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-requires tumor-specific therapy-->Ag modulation would potentially interfere w/ malignant phenotype
1. overexpressed proto-oncogenes e.g. EGFR, HER2 2. Point mutations e.g. ras, B-caterin, CDC27, CDK4, Bcr/Abl 3. Viral Ag: HPV, EBV, Hep B |
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DC Maturation Factors
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-T cell signals: CD40L
-Microbial stimuli: TLR ligands, LPS, peptidoglycans, etc -Inflammatory cytokines: TNF, IFN |
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tumor resistance to immune response
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1. loss of Ag presentation capacity by tumor
2. tumor access may be limited due to poor vascularity 3.intrinsic resistance (anti-apoptotic genes) -->resistance to death receptor pathways (reduction in Fas receptor; increased c-FLIP; lose TRAIL) 4. upreg of "survival" pathways -->akt, Bcl-2 5. Ag modulation 6. Loss of tumor Ag expression: tumor heterogeneity 7. tumor cell or tumor-assoc Macrophage (TAMs) prod of local factors that suppress T cell responses (TGF-b) and DCs (VEGF, IL-10) 8. tumors induce/recruit Tregs which suppress T cells |
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define "cross priming"
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-Ag presentation to T cells in LN
-induction of anti-tumor T cell response |
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CD8+ and tumor cells
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-CD8 CTL can recognize Class I-peptide complex and induce tumor lysis and apoptosis (perforin/granzyme)
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alterations in Ag processing
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-loss/down reg of Class I (30-70%)
-TAP/proteosome loss (10-80%) -IFN-gR signaling defect (rare) |
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seed and soil hypothesis
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-stromal inflammation as tumor "promoter"
-"tolerogenic" healing/remodeling/repair -some inflammation stimulates malignancy e.g schistosomiasis & bladder cancer H. pylori & gastric cancer |
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TAMs
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-tumor-assoc macrophages
-generate immuno-suppressive cytokines (as does tumor itself)-e.g. IL-10, TGF-b |
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explain the role of Tregs
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-tumor cells produce CCL22 to recruit Tregs--do the "dirty work" for tumor to suppress immune response
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Mac products that drive tumorogenesis
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-Growth and survival (FGF, EGF...)
-Angiogenesis (VEGF...) -Tissue Invasion and metastases (PGE2, chemokines) -Mutations (superoxide) -Inhibition of T cell responses |
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Anti-CTLA4 Abs
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15% clinical response in melanoma, prostate, etc.
-autoimmunity seen in many patients -possible combined therapy with tumor vaccines |
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other new treatments-immuno stimulatory
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-Treg depletion-IL-2 diptheria toxin conjugate
-Anti-PD-1: reversal of T cell exhaustion (Passive) -Adoptive transfer of T cells (uses patient’s own T cells, expanded in vitro to large number of effector CD8 T cells) -Monoclonal & engineered Abs |
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what is PD-1 anyway?
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-a B7 receptor that is found on activated memory T cells
-high levels of PD-1 can block memory T-cell activation, leading to T cell exhaustion |
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Rationale for monoclonal Abs
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-Abs to antigens like Her2/NEU, CD20, BCR, EGFR, VEGF
-"smart bomb"-->Abs can be conjugated to chemotherapeutic abs or radionucleotides -directed ab therapy can be used to deliver toxic payloads |
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Active immunization
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1. injection of modified irradiated tumor cells
2. injection of DCs that have been cultured and incubated with tumor cells and induction factors 3. injection of tumor Ags + immunostimulatory molecules |
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"the adjuvant effect"
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-immunology's "dirty little secret"
-effective immunization usually requires mixing Ag with agents which both promote uptake of Ag by APCs as well as activate and recruit APCs to vaccine site -classic adjuvants: alum or mineral oil -molecular adjuvants: TLR ligands, CD40L |
