Cancer and the Immune System - PowerPoint Presentation

1. Cancer and the Immune SystemDr. Refif S. Al-Shawk 2023After reading this lecture, you should be able to: Demonstrate how specific innate and adaptive immune response pathways and molecules are involved in the recognition and eradication of cancer cellsExplain the immune recognition of tumor-associated antigens and tumor-specific antigens. Explain the various phases of cancer immunoeditingEvaluate and estimate the effectiveness of new immune-based anti-cancer therapy.

2. Cancer is altered self-cells that have escaped normal growth-regulating mechanisms.These cells give rise to clones of cells that can expand to a considerable size, producing a tumor, or neoplasm.If it does not invade the healthy surrounding tissue it is called benign.A tumor that continues to grow and becomes progressively invasive is malignant

3. TUMOR ANTIGENS The classification of tumor antigens was based on their patterns of expression. Tumor antigens recognized by human T-cells fall into four groups based on their source: Antigens encoded by genes exclusively expressed by tumors (e.g., viral genes)Antigens encoded by variant forms of normal genes that are altered by mutation Antigens normally expressed only at certain stages of developmentAntigens that are overexpressed in particular tumors Antigens that are expressed on tumor cells but not on normal cells are called tumor-specific antigens; the first two above, some of these antigens are unique to individual tumors, whereas others are shared among tumors of the same type. Tumor antigens that are also expressed on normal cells are called tumor-associated antigens; the second two above, in most cases, these antigens are normal cellular constituents whose expression is aberrant or dysregulated in tumors.

4. Tumor Antigens:  Tumor-specific Ag (TSAs), which, is unique to tumor cells & not found in a normal cell. Viral HPV: L1, E6, E7 ----- Cervical carcinoma HBV: HBsAg. ------ Hepatocellular carcinoma   Tumor-associated Ag (TAAs), which is not unique to the tumor but, maybe a protein that is expressed on normal cells  also, which are: Differentiation Stage (Oncofetal Ag) as:Alpha-fetoprotein (AFP), is normally present only during fetal life so, if it ↑ in adult life, it indicates liver cancer.                        Carcinoembryonic Ag (CEA) which, if ↑ in adults so, indicates colorectal carcinoma. Overexpression of normal Ag, as growth factor & growth factor receptor.The epidermal growth factor (EGF) receptor is at levels 100 times greater than in normal cells.PSA (prostate)

5. Tumor-Specific Antigens Contain Unique Sequences Tumor-specific antigens are unique proteins that may result from DNA mutations in tumor cells that generate altered proteins and, therefore, new non-self antigens or epitopes. Cytosolic processing of these proteins then gives rise to novel peptides that are presented with MHC class I molecules, which can lead to the induction of a cell-mediated response by tumor-specific CD8 T cells. TSAs contain some “foreign” or new peptides and thus become natural targets for immune recognition. TSAs can be found in some virally induced tumors, where sequences from the infecting virus are recognized by the immune system. These unique sequences will be shared by all tumors induced by the same virus, making their characterization simpler. In some cases, the presence of virus-specific tumor antigens is an indicator of neoplastic transformation. HPV E6 and E7 proteins are found in more than 80% of invasive cervical cancers, and they provide the clearest example of a virally encoded TSA.

6. Tumor-Associated Antigens Are Normal Cellular Proteins with Unique Expression Patterns Tumor-associated antigens, or TAAs, are not unique to neoplastic cells. Instead, these represent normal cellular proteins and thus are prone to the usual self-tolerance mechanisms. Most TAAs are proteins expressed only during specific developmental stages, such as in the fetus, or at extremely low levelsWhen the transformation of cells causes these fetal proteins to appear at later stages of development on the neoplastic cells of the adult, they can be recognized as aberrant and induce an immunologic response. In some instances, these can be recognized by the immune system or used clinically to monitor or therapeutically target cancer.

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8. Immune responses to cancerInnate and adaptive pathways participate in cancer detection and eradication Adaptive immune responses, mainly mediated by T cells, have been shown to control the development and progression of malignant tumors. HOW??

9. Immunoediting Can Both Protect Against and Promote Tumor Growth Three proposed mechanisms by which the immune system control or inhibit cancer: By destroying viruses that are known to transform cellsBy rapidly eliminating pathogens and regulating inflammation By actively identifying and eliminating transformed cells (involving tumor cell identification and eradication, which is termed immunosurveillance)

10. Innate and Adaptive Pathways Participate in Cancer Detection and Eradication Many of the elements of both innate and adaptive immunity can be linked in some way to tumor cell recognition and destruction, certain components appear to play key roles in immune-mediated cancer control there are both “good” and “bad” forms of responses to cancer. The good or antitumor: innate responses dominated by immune-activating macrophages (called M1)- cross-presenting dendritic cells, and NK cells - These cells and the cytokines they produce help elicit strong TH1 and CTL responses, which are associated with a good prognosis and tumor regression. Conversely, in tumors that are more likely to progress and metastasize, the immune cell infiltrates include anti-inflammatory macrophages (M2) and myeloid-derived suppressor cells (MDSCs). Concomitantly, adaptive responses to cancer dominated by the TH2 pathway (and in some cases, also TH17 or TREG cells) are associated with poorer clinical outcomes and reduced survival times.

11. Innate Inhibitors of Cancer :NK Cells NK cell recognition mechanisms use a series of surface receptors that respond to a combination of activating and inhibiting signals delivered by self-cells :Many transforming viruses can induce the down-regulation of MHC expression, detecting “missing self” is likely at least one of the ways in which NK cells participate in tumor cell identification and eradication. Inducing signals on tumor cells in the form of changes in protein expression, like danger- or damage-associated molecular patterns (DAMPs), can also engage NK cell–activating receptors (e.g., NKG2D) delivering what is referred to as an “altered” or “induced-self” signal Various forms of cellular stress, including viral infection, heat shock, UV radiation, and other agents that induce DNA damage, can trigger the expression of the ligands for these activating NK-cell receptors. When activating signals are induced by DNA damage pathways, NK cells may be able to distinguish cancerous or precancerous cells from healthy neighboring cells. Once engaged, these cells use cytolytic granules, which include compounds like perforin, to kill target tumor cells. NK cells may also participate in cancer eradication by secreting IFN-γ, a potent anticancer cytokine that encourages MHC expression in DCs, which in turn stimulates strong CTL responses.

12. macrophagesActivated macrophages play a significant role in the immune response to tumors. Macrophages are often observed to cluster around tumors, and the presence of proinflammatory macrophages, such as the M1 type, is correlated with tumor regression, HOW?macrophages express Fc receptors, enabling them to recognize antibodies bound to tumor antigens and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). The antitumor activity of activated macrophages is likely mediated by lytic enzymes, as well as reactive oxygen and nitrogen intermediates. In addition, activated macrophages secrete tumor necrosis factor alpha (TNF-α), a cytokine with potent antitumor activity.

13. Adaptive Cellular Processes and the Cells Involved in Cancer Eradication CTLsTumor antigens induce humoral and cell-mediated immune responses that lead to the destruction of transformed cells expressing these proteins. Several tumors have been shown to induce CTLs that recognize tumor antigens presented by MHC class I on these neoplastic cells. In fact, strong antitumor CTL activity correlates significantly with tumor remission and is primarily credited with maintaining the equilibrium phase of cancer immunoediting, where neoplastic cell survival and death are fairly balanced. CD8+ T cells rarely work alone, suggesting that activated DCs and TH1-type cells must also be involved in fostering this CTL response. high frequency of tumor-specific CD8+ T cells, or an elevated ratio of CTL to TREG cells, is associated with enhanced survival and cancer eradication

14. B cellsB cells respond to tumor-specific antigens by generating anti-tumor antibodies that can foster tumor cell recognition and lysis. Using their Fc receptors, NK cells and macrophages participate in this response, mediating ADCC Some anti-tumor antibodies, called enhancing antibodies, serve a more detrimental role, blocking CTL access to tumor-specific antigens and enhancing the survival of the cancerous cells.

15. CytokinesIFN-γ. This cytokine can exert direct anti-tumor effects on transformed cells, including enhanced class I MHC expression, making neoplastic cells better targets for CD8+ T cell recognition and destruction. The cytokine IL-12 has the ability to enhance anti-tumor immunity by driving the development to T-cell pathways: this cytokine encourages DCs to activate strong TH1 and CTL responses. TNF-α induced hemorrhage and necrosis of the tumor.Studies on animal models found eosinophils, along with the cytokine produced by these cells, IL-5, involved in cancer recognition and removal

16. Cancer immunoeditingIn immunoediting, the immune system engages in both positive (antitumor) and negative (protumor) actions that help to sculpt the tumor, determining which cells will be eliminated and which will remain. Cancer immunoediting can be divided into three sequential phases: elimination, equilibrium, and escape. The first phase, elimination, is the traditional view of the role of the immune system in cancer, roughly analogous to immunosurveillance—identification and destruction of newly formed cancer cells. Equilibrium is the next phase, characterized by a state of balance between the moderate destruction of neoplastic cells and with the survival of a small number of cancer cells. Phase III (escape): Further mutation in the surviving tumor cells leads to the capacity for immortal growth and metastasis. Over time, inhibitory immune responses begin to dominate, and immune activity shifts from anti- to protumor.

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18. Some Immune Response Elements Can Promote Cancer Survival Leukocyte infiltration is important for tumor eradication; however, prolonged chronic inflammation and tumor-enhancing antibodies correlate negatively with survival. The presence of immunosuppressive cells (e.g., M2 macrophages, and TREG cells) and the cytokines they produce (e.g., IL-10 and TGF-β) in the tumor microenvironment fosters tumor survival and immune evasion.

19. Tumor Cells Evolve to Evade Immune Recognition and Apoptosis The fact that so many individuals die each year from cancer suggests that the immune response to tumors is often ineffective. The selective pressure applied by the antitumor immune response can select for escape mutants or cells that evade the immune response. (immunoediting). Reduced MHC Expression in Tumor Cells Poor Costimulatory Signals and Immunosuppressive MicroenvironmentsTumor Cell Resistance to Apoptotic Signals

20. Tumor evasion of the immune system:Reduced MHC Expression in Tumor Cells Immune responses to tumor cells impart selective pressures that result in the survival and outgrowth of variant tumor cells with reduced immunogenicity, a process that has been called tumor immunoediting. loss of tumor-specific antigens- class I MHC expression may be downregulated on tumor cells so that they cannot be recognized by CTLs. 

21. Poor Costimulatory Signals and Immunosuppressive MicroenvironmentsTumors may engage inhibitory mechanisms that suppress immune responses. T- cell responses to some tumors are inhibited by the involvement of CTLA-4 one of the inhibitory pathways in T cells.Secreted products of tumor cells may suppress anti-tumor immune responses. An example of an immunosuppressive tumor product is TGF-β, which is secreted in large quantities by many tumors and inhibits the proliferation and effector functions of lymphocytes and macrophagesRegulatory T cells may suppress T cell responses to tumors. The number of regulatory T cells are increased in tumor-bearing individuals, and these cells can be found in the cellular infiltrates in certain tumors. Tumor-associated macrophages may promote tumor growth and invasiveness by altering the tissue microenvironment and by suppressing T-cell responses.*These macrophages have a phenotype that secretes mediators, such as IL-10 and prostaglandin E2, that impair T cell activation and effector functions. *Tumor-associated macrophages also secrete factors that promote angiogenesis, such as TGF-β, which may enhance tumor growth.

22. Tumor Cell Resistance to Apoptotic Signals changes in the extrinsic response system, namely cell-surface death receptors, as well as intrinsic mechanisms based on mitochondrial pathways of apoptosis. The Fas cell death receptor (CD95) and NKG2D engaged by NK cells, all receive external signals for the induction of programmed cell death. Defects in any of these components will therefore inhibit the induction of this pathway.

23. Anticancer Immunotherapies Present-day cancer treatments take many forms. solid tumors, surgical removal, and local radiation are often employed. Frequently added to this are various drugs or other small-molecule inhibitors designed to target residual or metastatic tumor cells, called adjuvant cancer therapy. Immunotherapies. Any treatment designed to specifically revive, initiate, or supplement in vivo antitumor immune responses. Which focuses on activating an immune response against the cancer cells, creating signals or cells that will guide the immune system in the right direction.humanized monoclonal antibodies that will bind selectively to: cancer cells, peptides from tumor antigens administered in a way that induces CTL activity, or molecules that release cancer-generated blocks to natural immune activation. Immunotherapy is used as an immune-boosting component, added to standard regimens of surgery, radiation, and/or chemotherapy.

24. immunotherapy to treat cancer can take many forms, including monoclonal antibodies that target specific surface molecules (either naked or with toxins conjugated)adoptively transferred autologous DCs that have been loaded with TAAs and expanded in vitro, followed by reinfusion into the patient;adoptively transferred T cells that have been collected from the patient and expanded or modified in vitro, and then reintroducedCAR T cells are generated by adding a chimeric receptor recognizing a tumor antigen to autologous T cells that are expanded and later re-infused checkpoint blockade, involving the use of mAbs specific for one or more of the surface molecules (CTLA-4, PD-1, or PD-L1) involved in regulating or dampening immune activity.

25. Monoclonal antibodyA monoclonal antibody (mAb) is an antibody produced from a cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell.Monoclonal antibodies can have monovalent affinity, binding only to the same epitope (the part of an antigen that is recognized by the antibody). In contrast, polyclonal antibodies bind to multiple epitopes and are usually made by several different antibody-secreting plasma cell lineages. It is possible to produce monoclonal antibodies that specifically bind to virtually any suitable substance; they can then serve to detect or purify it. This capability has become an investigative tool in biochemistry, molecular biology, and medicine. Monoclonal antibodies are being used on a clinical level for both the diagnosis and therapy of several diseases.

26. References:Immunology , Kuby, eighth edition 2019Medical microbiology, Jawetz, 26th editionCellular and Molecular Immunology, Abul K. Abbas, 8th edition.