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Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
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Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

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Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy. Objectives. What are the tumor antigens recognized by the immune system? How does the immune system recognize and react to tumors? How do tumors evade the immune systems?. - PowerPoint PPT Presentation
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Page 1: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Immunology of lung cancer

BYSamiha Mohamed Abo-Bkr

Prof.of chest diseasesAl-Azhar univeristy

Page 2: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Objectives

• What are the tumor antigens recognized by the immune system?

• How does the immune system recognize and react to tumors?

• How do tumors evade the immune systems?

Page 3: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
Page 4: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

What are the tumor antigens recognized

by the immune system?

Page 5: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
Page 6: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

How does the immune system recognize and

react to tumors?

Page 7: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Cancer Immunosurvailance

• The hypothesis was first proposed by Ehrlich in 1909, and modified by Thomas and Burnet in 1957.

• Immunosurvailence: the immunological resistance of the host against the development of cancer.

• Now referred to “cancer immunoediting”encompassing 3 phases: elimination, equilibrium and escape.

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Antitumor immune responses• The two branches of the immune response – humoral

and cell-mediated – act both independently and in concert to combat tumour progression, the success of which depends on the immunogenicity of the tumour cells.

• The immune system discriminates between transformed cells and normal cells by virtue of the presence of unique antigens on tumour cells.

• Despite this, the immune system is not always able to detect and kill cancerous cells because neoplasms have also evolved various strategies to escape immune surveillance.

• The tumouricidal role of various components of the immune system, include macrophages, lymphocytes, dendritic cells and complement."

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Page 17: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
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Page 19: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

How do tumors evade the

immune system?

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Page 21: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
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Page 26: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy
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Page 28: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

LUNG CANCER

Page 29: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of Smoking• Cigarette smoke has both pro-inflammatory

and immunosuppressive effects on the immune system.

• Smoke promotes inflammation by its acute effect on macrophages and epithelial cells as it induces the recruitment of cells from the microcirculation to the lungs.

• At the same time, cigarette smoke impairs innate defense mechanisms that are mediated by macrophages, epithelial cells, dendritic cells (DCs) and natural killer (NK) cells, thereby increasing the risk, severity and duration of infection.

Page 30: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

• After long-term exposure to cigarette smoke, lymphoid aggregates with T cells and B cell zones form at the site, supporting the production of pathogenic autoantibodies and driving autoimmune disease.

• Moreover,Loss of mucosal defenses lead to bacterial colonization (as occurs in around 30% of long-term smokers with chronic obstructive pulmonary disease (COPD)).

• Concurrently, somatic mutations in the epithelium and alteration of macrophage phenotype promote inflammation and thus the development of cancer (carcinoma in situ) that has a high chance of metastatic spread.

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Antitumor immune responses

Page 35: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Immune response to tumour antigens

• The quality and quantity of the immune response evoked is determined by the nature of antigens expressed by the tumor.

• For example, carbohydrate antigens induce highly potent humoral IR, while protein antigens establish a CMIR.

• Furthermore, the immunogenicity of a particular tumor depends on the processing of its antigens and the presentation of its peptides to CTLs by MHC class I molecules.

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Cont. Immune response to tumour antigens

• As tumour growth progresses, parts of the tumour become necrotic and soluble tumour antigens are released.

• By this time, the tumour reacha threshold size against which any immune response is impotent.

• Thus, for an effective antitumor immune response, it is necessary for the tumour antigens to be accessible to the effector cells of the host at an early enough stage in tumor development.

Page 37: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

• Cell-mediated immunity (CMI) is a term coined to describe any immune response in which Abs play a subordinate role.

• The effector cell types implicated in the tumour rejection process are cytotoxic T lymphocytes (CTLs), Ab-dependent killer cells, natural killer (NK) cells and macrophages, all of which act either alone or together with other cell types.

• Tumour destruction results from three major mechanisms:

(1) destruction of the tumour by necrosis mediated by polymorphonuclear leukocytes;

(2) indirect inhibition of angiogenesis by secondary interferon γ (IFN-γ), tumour necrosis factor α (TNF-α) and chemokines;

(3) activation of leukocyte subsets capable of producing proinflammatory cytokines, CTLs and antitumour Abs.

The cellular immune

response and

tumour cells

Page 38: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of CTLs• The cytotoxic T lymphocyte (CTL) bind with their

T-cell receptor (TCR) to the major histocompatibility complex (MHC) class I molecules expressed with the tumor peptide on the tumour cell surface.

• The interaction also involves binding between adhesion molecules, such as intercellular cell adhesion molecule 1 (ICAM-1) with leukocyte function-associated antigen 1 (LFA-1), and Fas (CD95) with Fas ligand (CD95L).

• The tumour cell destruction is affected by the

release of perforins (pore-forming proteins), serine esterases, interferon γ (IFN-γ), granzyme B and/or tumour necrosis factor α (TNF-α) by CTLs.

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Role of CTLs

Page 40: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of NK cells• The term ‘natural killer' refers to cells other than

macrophages and polymorphonuclear leukocytes that are cytotoxic to neoplastic or non-neoplastic targets in absence of specific TCR activation by the antigen.

• NK cells provide the first line of defencse in both normal and T-cell-deficient hosts.

• This is because, unlike T cells, they do not require processing and presentation of antigen along with MHC molecules.

• In consequence, NK cells kill targets that have managed to escape T-cell mediated killing because they do not express the appropriate MHC molecule.

• The mechanism of NK-mediated oncolysis involves recognition and conjugation of effector to target, delivery of death signals, and disintegration and death of the target cells. Some tumours specifically stimulate NK cells by producing IFN, which activates NK-cell tumouricidal activity .

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Page 42: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of macrophages• Macrophages mediate both ADCC and the

nonspecific killing of tumour cells .• Macrophage-mediated cytotoxicity is most efficient

when cell-to-cell contact is established, but several cytotoxic soluble factors were also found to play a role.

• Activated macrophage cytotoxicity against tumor dependson nitrite ion synthesis.

• Nitric oxide (NO) is able to inhibit mitochondrial respiration, prevent DNA replication and denature essential iron–sulphur-containing enzymes present in target cells.

• Other antitumour products secreted by macrophages include TNF, hydrogen peroxide (H2O2) and FasL (CD95L), which are essential for macrophage cytotoxicity

Page 43: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of DCs• DCs function as APCs .

• The presence of DCs in tumor infiltrates is a good prognostic factor, and interaction between them produces antitumor cytokines.

• Inhibition of metastatsis might depend on entry of DCs into the tumour, and the release of NO and other inhibitory cytokines.

• Conversely, a failure of DCs to enter tumours might be because of the ability of the tumour to produce cytokines that inhibit NO production .

• In patients with stage III squamous cell carcinoma, a significantly better survival after radiation therapy was observed when infiltrating Langerhans cells were observed in tumour tissues.

• Recently antigen-pulsed DCs could directly sensitise T cells and stimulate the development of antigen-specific immune responses, leading tot protective and therapeutic antitumour responses.

Page 44: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of B cells

B cells infiltrating cancer tissues

produce IgG that recognises a common

tumour antigen

Page 45: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of humoral immune response • Humoral immunity is mediated by Abs produced by B

cells. • Abs specifically recognise and neutralise antigens, and

can be transferred to individuals by injecting either plasma or serum.

• Complement surveillance may extend to tumor cells escaping into the blood from their original site but this hasn’t yet been examined.

• In principle, Activation of complement can lead to direct lysis of the target cells through complement fixation.This is mediated via classical pathway, after binding of Abs to the target cells, or via alternative pathway, whereby deposition of C3b, inactivated C3b (iC3b) and, C1q or C4b on the target cell surface facilitates phagocytosis and other complement-dependent cellular cytotoxicities.

Page 46: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Role of cytokines• Cytokines are powerful regulators of both normal cell behaviour

and host immune response against cancers.

• The activity of Th-cell populations and their cytokine products, significantly affect the immune response to tumors. They play a decisive role in the progression or regression of a tumour.

• Th1 cells preferentially secrete IFN-γ and IL-2, and are responsible for CMI

• Th2 cells produce IL-4, IL-5, IL-6 and IL-10, and enhance the humoral response.

• Th3 produce TGF-β , IL-4 and IL-10, enhancing immunosuppressive functions.

• There is an antagonistic effect between Th1- and Th2-cell populations as the cytokines produced by one population nullify the proliferation and function of cells of the other type.

Page 47: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

• Regressing the tumor shows a predominant CD4/Th1-type of cytokine response, whereIL-2, IL-12, IFN-γ and TNF-α are found at high levels.

• The tumor regression is primarily NK-cell-mediated. NK cells are unable to kill tumour cells until they are activated with IL-2, IL-12 and IFN-γ.

• Cytokine levels at the tumor site were several fold higher than in the circulation, suggesting their important role in the maintenance of tumor infiltrating lymphocytes in an activated state against the tumor.

Cont.Role of cytokines

Page 48: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Tumor evasion of immune system

Page 49: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Tumor evasion of immune system

• Tumors possess tumor rejection antigens that are still capable of escaping destruction by host immunity

• Some tumors escape immune destruction using immunological ignorance mechanisms, others avoid confrontation with host effector cells by secreting anti-inflammatory and immunosuppressive factors, and others induce apoptosis of effector cells.

Page 50: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Alteration in MHC (HLA) peptide complex

Page 51: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

• One of the most potent immunosuppressive factors is TGF-β .

• TGF-β affects proliferation, activation and differentiation of the cells participating in both innate and acquired immunity.

• TGF-β inhibits immunoregulatory cytokine

production , including IL-12 production by monocytes.

• TGF-β is a potent inhibitor of CTL differentiation , thus inhibiting development of tumour-reactive CTLs.TGF-β is also a potent inhibitor of the proliferation of neoplastic cells in vitro. So this cytokine might exert dual effects on tumour growth.

Immunosuppression

Page 52: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

Apoptosis• The Fas–FasL interaction is involved in

the induction of apoptosis.

• Fas is a cell surface bound member of the TNF receptor superfamily and, upon engagement by its ligand FasL, mediates apoptosis of the Fas-expressing cell .

• Some tumors have counterattack mechanisms. The tumor cells express functional FasL which resist s Fas- FasL mediated T-cell cytotoxicity and mediates the peripheral deletion of tumour-reactive T-cell clones.

Page 53: Immunology of lung cancer BY Samiha Mohamed Abo-Bkr Prof.of chest diseases Al-Azhar univeristy

To insure good health: Eat lightly, breathe deeply, live moderately, cultivate cheerfulness, and maintain an interest in life. 

William Londen

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