Session 26 - Tumor Immunology.pptx

TUMOR IMMUNOLOGY Carolina Mendoza, MD PBC 9700 Adapted from PowerPoint by Dr. R. Gregg Learning objectives 1. Identify the steps leading to the transformation of healthy cells into abnormal, cancerous cells. 2. Compare and contrast the characteristics of tumor-specific and tumor-associated antigens....

TUMOR IMMUNOLOGY Carolina Mendoza, MD PBC 9700 Adapted from PowerPoint by Dr. R. Gregg Learning objectives 1. Identify the steps leading to the transformation of healthy cells into abnormal, cancerous cells. 2. Compare and contrast the characteristics of tumor-specific and tumor-associated antigens. 3. Identify the roles of antigen presenting cells, natural killer cells, phagocytes, T cells and B cells in cancer development, control and eradication. 4. Define tumor editing and antigen loss variant. 5. Identify the mechanisms employed by tumors to evade natural killer cell cytotoxicity. 6. Identify the mechanisms employed by tumors to evade dendritic cell-mediated activation of T cells. 7. Identify factors in the tumor microenvironment that facilitate tumor escape from immune response. 8. Identify approaches to stimulate immune responses against resistant tumors. 2 Transformation of “normal” cells 3 Genes associated with growth and survival Genes associated with cell cycle regulation, proliferation and survival  Tumor suppressor genes – when mutant the affected cell can move on through the cell cycle without DNA repair (often mutations in DNA repair systems evident in cancer cells)  Proto-oncogenes – when activated they stimulate cell proliferation and growth  Programmed cell death – when active (Bcl-2, Bcl-XL) or inactive (Bax, Bim, Puma) then cells can avoid the mitochondrial pathway of cell death 4 Key features of all cancer cells 5 HOW DOES THE BODY MOUNT A RESPONSE TO CANCER? 6 Much of the work to answer this question performed by James P. Allison, PhD 1980s – identified that T cells could recognize Ag through a TCR 1992 – identified co-stimulation through B7-CD28 1995 – demonstrated that CTLA-4 could outcompete CD28 and slow T cell responses 2011 – Ipilimumab (anti-CTLA-4) or Yervoy  2015 – Nivolumab (anti-PD-1) or Opdivo  FDA approved for advanced melanoma FDA approved for kidney cancer, lung cancer, melanoma (& Hodgkin lymphoma in 2016) 2018 – Awarded Nobel Prize in Physiology or Medicine (first to stimulate immunity against cancer) 7 Immune cells must “recognize” cancer cells as different from normal cells to be effective 8 Tumor Specific Antigens (TSA) Altered self-peptide Self-peptide MHC class I Normal Cell Tumor Cell (mutation generates a “new” peptide) 9 Tumors expressing TSA have a better prognosis Unique Ag expressed by tumors (i.e. altered self-peptides) Strong immunogenicity Most common in tumors induced by:  Chemical & physical carcinogens  Oncoviruses o EBV, HTLV-1, HPV, HBV, HCV Tumors with high levels of TSA are ELIMINATED 10 Tumor Associated Antigens (TAA) Overexpressed self-peptide Self-peptide MHC class I Normal Cell Tumor Cell (gene alteration results in overexpression of a self protein) 11 Tumors expressing more TAA are more difficult for tumor immunity to eliminate TAA proteins Overexpressed self-peptide  Self-Ag usually expressed at low levels in normal cells – overexpressed in tumor cells o Growth factors o Growth factor receptors Hu epidermal growth factor receptor 2 (HER2 or Neu) o Oncogene-encoded proteins o Differentiation proteins Melanoma – Tyrosinase, gp100, Melan-A, MART-1 12 Some TAA can still be adequate T cell targets (overexpressed developmental Ags) TAA proteins Overexpressed self-peptide  Oncofetal Ags o Ags of embryonic development before immune system maturation o Recognized in cancer cells as “non-self” o EX – Alpha-fetoprotein (AFP), Carcinoembryonic Ag (CEA), Melanoma Ags (MAGE-1-3, BAGE, GAGE-1/2) Most liver cancer patients have elevated serum levels of AFP 90% of colorectal cancer patients have elevated serum levels of CEA Only trace amounts of both in normal and some non-cancer disease states 13 Most tumors with TAA have a poor prognosis Non-immunogenic or weak immunogenicity Useful as diagnostic or prognostic markers  Example – CEA o Serum CEA monitored following colorectal carcinoma removal o Increase in serum CEA tumor growth Serum concentrations correlate with:  Tumor size  Lesion differentiation  Response to therapy 14 Effector mechanisms in tumor immunity Melanoma (in lung) 15 Immune response to cancer NK cells are activated by IL-2 or IL-12 (DC, macrophage) and express activation receptors to bind to tumor cells for release of perforin and granzyme Macrophages phagocytize and present tumor Ags and kill tumor cells by ROS, NO, lysosomal enzymes, TNF- NK cells also use FcR to bind to Ig (ADCC) Produce IFN-to activate macrophages CD8+ T cells differentiate into CTL which are effective at eliminating cancer cells by release of perforin and granzyme as well as Fas-FasL CD4+ T cells must differentiate into IFN-producing Th1 cells (activate macrophages and upregulates MHC I on tumor cells) IL2 produced by Th cells drive expansion of anti-cancer CD8+ T cells Anti-cancer Ig can bind to tumor Ags on the cancer cells to trigger complement activation or ADCC Little evidence indicates that Ig can control and eliminate tumors Dendritic cells capture tumor Ag (released by tumor or macrophage) and present to CD4+ and CD8+ T cells Must be mature (provide 3 signals) 16 Immunosurveillance by NK cells Expression of MHC I on normal host cells prevents NK cell lysis (inhibitory signal > stimulatory signal) 17 Transformation renders cells susceptible to NK cell lysis NK cell kills target cell  No inhibitory receptor engagement  Loss of MHC class I  (No inhibitory signal provided) Transformation 18 Cytokines can “prime” NK cells for cytotoxicity NK cell activated by cytokines (IL-2, IL12, IL-15, IL-21) express activation receptors (NKG2D) NK cell kills target cell  Stimulatory receptors  (stimulatory signal > inhibitory signal) Stress-induced ligands (MICA, MICB, others)  Transformation 19 Antibody function in tumor immunity (Opsonization and Antibody dependent cellular cytotoxicity) 20 Selective pressure by immunity can promote tumor growth and survival Tumor editing or immunoediting One consequence of the specificity of immune responses is the selective elimination of tumor cell clones that express high levels of tumor Ag and MHC class I molecules Thus, tumor cell clones that express low MHC I and tumor Ags survive CTL cytotoxicity These surviving tumor cell clones or Ag loss variants now have a greater resistance to host immunity and can expand to fill the void left by the destroyed cancer cells – often these cells will express low levels of TAA and little to no TSA 21 Tumor release of soluble stress proteins can aid evasion of NK cells and CTL 22 Some cancer cells in a tumor can reduce MHC class I surface expression Decreased synthesis of alterations of the structure of MHC class I molecules Lack of  -2 macroglobulin and TAP molecules prevent MHC class I expression Without MHC class I – CTL cannot locate cancer cells and induce apoptosis However, MHC class I low or negative cancer cells are detectable by NK cells Some cancer cells produce IL-10 and/or TGF-to suppress NK cell proliferation and function Tumors can upregulate HLA-E which binds NK inhibitory receptors and prevents NK cell functions 23 Tumor DC are low in number and immature Action of vascular endothelial growth factor (VEGF) Limited maturation T cells are anergic Reduced numbers of immature DC 24 T cell responses and tumors Th1 Treg Th2 IFN- Cancer Destruction IL-4 Cancer Persistence IL-17 IL-22 Unclear CD4+ CD25+ Foxp3+ Th17 25 Tumor infiltrating T cells deviated to Th2 and Treg cells Th1 Th Th Th Th Th Treg Th2 Th17 26 Tumor microenvironment (TME) is the battlefront 27 Tumor can produce cytokines Tumor can produce: IL-10 TGF- GM-CSF VEGF Chemokines 28 Tumor cytokines generate a hostile environment TGF- Induces Foxp3 iTreg cells (TGF- ) IL-10 Low B7, MHC II, IL-12 IL-10 Differentiate into Th2 (IL-4, IL-10) Tr1 (IL-10) IL-10 Promote TAMs GM-CSF IL-6 Monocytic PGE2 precursor Gr1+ CD11b+ IL-10 TGF- GM-CSF VEGF Chemokines VEGF 29 Cancer-associated fibroblasts support tumor growth and metastasis CAF: Produce ECM and MMP for tumor spread Growth factors VEGF TGF- IL-6 CXCL12 to recruit natural Treg cells 30 Immunoregulation in the tumor Natural Treg cells (CD4+ CD25+ Foxp3+) Recruited to the tumor in high numbers Activated by tumor Ag Suppress all infiltrating immune cells (DC, T cells, macrophages) Myeloid-derived suppressor cells (MDSC – Gr1+ CD11b+) Tumor associated macrophage (TAM) Recruited from blood or tissue resident Polarized to M2-like TAM by IL4 or IL-13 (Th2) and IL-10 (Tr1) in the TME Produce IL-6, IL-17, IL-23 to drive STAT-3-dependent tumor growth Arg-1 and NO to diminish diminishes CTL Arg-1 (loss of arginine to block T cell activation) Express PD-L1 to bind CTL PD-1 iNOS (NO reacts with TCR to reduce signaling) Produce ECM for tumor spread TGF- VEGF IL-10 IDO (loss of tryptophan to block T cell activation) 31 Approaches to overcome tumor escape 32 Cytokine therapies IL-2 IFN- Induce MHC class I on tumors Mature subsets of DC Anti-angiogenic Promote direct apoptosis of tumors Approved for melanoma, hairy cell leukemia, chronic myelogenous leukemia Mediator of hematopoiesis & monocyte-macrophage differentiation Mature DC Most effective upon direct delivery into tumor (MDSC otherwise) Approved for recovery of PMN following chemotherapy induction Promote activation/expansion of T cells and NK cells Promote early B cell activation/expansion for Ig production Approved for metastatic melanoma & renal cell carcinoma (& metastatic renal cancer) IL-7, IL-15 & IL-21 in clinical trials GM-CSF TNF- Induce direct apoptosis & lysis of tumors Mature DC Anti-angiogenic Most effective upon direct delivery to tumor Tested in sarcoma & melanoma Septic shock possible 33 Immune checkpoint inhibitors (block the exhaustion signals through CTLA-4 and PD1) - Opdivo Keytruda - Yervoy 34 One immunotherapy approach is to block the ability of immune checkpoint proteins, to limit the strength and duration of immune responses These proteins normally keep immune responses in check by preventing overly intense responses that might damage normal cells as well as abnormal cells Tumors can commandeer these proteins and use them to suppress immune responses Blocking the activity of immune checkpoint proteins releases the "brakes" on the immune system, increasing its ability to destroy cancer cells 35 Adoptive cell therapy (ACT) Expands/rescues “anergic” tumorspecific T cells Reduces numbers of Treg cells Introduction of massive amounts of activated TIL (Tumor-Infiltrating Lymphocytes) which target tumor cells, but may be low in number in the tumor microenvironment to eradicate the tumor or overcome the immune suppressive signals present 36 ACT with CAR T cells CAR – chimeric antigen receptor CAR T cells are engineered to express receptors that bind to surface proteins on select cancer cells These receptors are multicomponent so as to activate the CAR T cell leading to effector functions such as perforin/granzyme release, Fas ligand expression and survival factors (Bcl) CAR T cells then have directed cytotoxic function against tumor cells without the need for antigen presentation and MHC class I on cancers 37