tumor immunology ........by Dr Palak.pptx

tumor immunology

1. Tumor Immunology : Dr Palak Borade (Post GRADUATE TRAINEE)

2. Contents Introduction History Cancer associated genes Tumor antigens Immunosurvelliance theory Immune response and evasion Treatment and prevention

3. Introduction : Tumour immunology describes the interaction between cells of the immune system with tumour cells.

4. In some pathologic conditions :

5. Cellular transformation and cancer

6. Tumor cells Antigen presenting cells Dendritic cells Look for CTL Identify naïve CD8 + CTl Lymphnode

7. Expresses to APC Activate CD8+CTL Specific tumor cell Kill directly

8. Cancer associated cells are divided into :

9. 1.Induction of cellular proliferation Some encode proteins induces cellular proliferation Some of these proteins function as growth factors or growth factor receptors

10. Induction of cellular proliferation In normal cells, the expression of growth factors and their receptors is carefully regulated Inappropriate expression of either a growth factor or its receptor can result in uncontrolled proliferation

11. 2.Inhibition of tumor suppressor gene

12. 3.Regulation of programmed cell death These gene encodes protein that either block or induce apoptosis Bcl-2 : an antiapoptotic gene

13. Cell intrinsic mechanism of tumor suppression : Cell intrinsic ‘ failsafe ’ systems that serve to curb the likelihood of cellular transformation occurring . This come into play when the abnormal signals are generated within cells and typically punish cells either through depriving them of the ability to divide a state called replicative senesce or through killing cells

14. Mechanism involved :

15. 1. Growth factor essential for cell division : Growth factors (GFs) are a group of proteins stimulating the growth of specific tissues. GF plays important roles in the regulation of cell division that drives cell proliferation . Each GF binds to a specific cell–surface receptor. A specific group of GF receptors possesses tyrosine kinases activity and is termed as receptor tyrosine kinases (RTKs).

16. 2.Telomerase shortening acts as a barrier t o cellular transformation : ‘ Hayflick Limit ‘ Problem Comes With Replicating The Extreme Tips Of Chromosomes Which Progressively Shortens With Each Round Of Of Cell Division . Sometimes Its Gets Eroded And Difficult To Fuse Together Cease To Divide Enter Proliferative Phase Natural Barrier

17. 3. Tumor suppressor monitor cell division : The product of tumor suppressor such as p53 and prb acts as another barrier to transform . These gene products are involved in signaling networks that monitor the integrity of the genome . They can hault the cycle either by DNA repair , cell cycle re –entry permanent cell arrest or cell death.

18. RTK plays most important roles in cell cycle regulation. RTKs are classified into 20 families. The most studied RTKs in terms of cell cycle include epidermal growth factor (EGF) receptor (EGFR) family, insulin receptor family, platelet-derived growth factor (PDGF) receptor (PDGFR) family, and nerve growth factor (NGF) receptor (NGFR). GFs drive cell cycle by activating RTKs and downstream signaling pathways, which regulates cyclin- Cdk complexes

19. Cell extrinsic mechanism of tumor suppression : The immune survelliance so that the altered cells with neoplastic potential could be identified and summarily eliminated .

20. 1. CT and Nk response Two primary approaches at our disposal , NK cells and cytotoxic Tcells . Two main strategies to kill :

21. Engage cell within target Fas ligand Stimulate Cognate receptors on tumor Apoptosis 2. Can engage

22. 2. NK mediated killing : tumor failing to express the normal complement of MHC molecule attract the attention of NK cells leading to cell mediated attacks . Upregulation of non classical MHC serve as a ligand for activating NK receptor . MHc molecule can be upregulated in response to viral infections as well as DNA damage these stress encounter may lead to expression of non classical MHC leading to MK mediated attack .

23. Tumor Antigens : Tumor transplantation antigens Tumor associated transplantation antigens

24. Tumor Antigens :

25. Virally controlled antigens : Proto-oncogene oncoprotein Critical function apoptosis Activated oncogenes apoptosis excessive proliferation

26. Expression of normally silent genes The dysregulated uncontrolled cell division of the cancer cell creates a milieu in which the products of normally silent genes may be expressed

27. Incidence of cancer would increase or the period of cancer would decrease , in the absence of functionalimmune system Immunosurveillance theory :

28. Immunosurveillance theory : Most cancer escape this because they are fundamentally “self”

29. The hypothesis states that a physiologic function of the immune cells is ito recognise and destroy transformed cells Cancer was noted to increased In patients recieveing long term immunosuppression because of a solid organ transplant

30. Anti – Tumor Immunesurvelliance Evidence : Tumors are more frequent in immunodeficient patients Transplanted patients Cancer more likely to appear in advanced stages

31. Immune Response

32. Factors That Tumors Exploit To Avoid Immune Responses. Immune suppression in the tumor microenvironment , mediated by CD4+regulatory T ells seems to be a major mechanism of tumor escapes Regulatory cells

33. Transforming growth factor (TGF)-B produced by tumor cells, aids conversion of CD4+Tcells into suppressive Tregs in situ Regulatory cells

34. Defective antigen presentation Down – modulating antigen processing machinery affecting the major histocompatibility complex (MHC) pathway

35. Expression of tumor antigen is downregulated ,which can lead to enhanced tumor incidence and metastasis because cytotoxic T lymphocyte can no longer recognise target antigens on the tumor cells Factors that tumors exploit to avoid immune responses

36. IMMUNE SUPPRESSIVE MEDIATORS Cancer produce several immune suppressive cytokines that suppresses CTL function TGF-B is a chief mediator of this activity , tumor necrosis factor (TNF) ,IL-1,IL-6,colony stimulating factor , IL-8,IL-10

37. Immune suppressive mediators Vascular endothelial growth factor inhibit maturation of DCs , thus affecting efficient uptake and antigen presentation

38. Factors that tumor exploit to avoid immune response Most tumor cells fail to express costimulatory molecules and can thereby induce energy

39. A number of studies have shown that cancer cells delete tumor – specifics CTLs through apoptosis

40. Cancer problems for immune perspectives :

41. Characterized by extensive infiltration of immune cells, and is regarded as a highly immunogenic tumor The complex milieu of the tumor microenvironment (TME) comprises of an extracellular matrix (ECM), a variety of stromal cells, and immune cells which synchronize and interact with tumor cells. Examples include tumor-associated macrophages (tams), regulatory T cells ( tregs ), cancer-associated fibroblasts ( cafs ) and endothelial cells Macrophages, dendritic cells ( dcs ), neutrophils, myeloid derived suppressor cells ( mdscs ), natural killer cells ( nks ), and innate lymphoid cells are the innate immune cells, and the adaptive immune cell comprises of T cells and B cells

42. Cross talk between the cells of the TME, ECM and the tumor cells is significantly responsible for fueling the tumor development In addition, the cancer-associated inflammation, more precisely chronic inflammation, involves inflammatory cytokines, chemokines and growth factors which could trigger DNA damage, tumor angiogenesis, and genomic instability, as well as the tussle between immunosuppression and promotion leading to tumorigenesis Furthermore, involvement of the - omic mechanisms plays a determinant role in extracting features describing the cellular and molecular heterogeneity of the TME and tumorigenesis

43. The process of both curtailing and promoting the tumor development by the immune system is referred as cancer immunoediting. Cancer immunoediting broadly comprises three phases, namely elimination (immunosurveillance), equilibrium, and escape The concept of cancer immunoediting is widely accepted, and tumor immune escape is considered an emerging hallmark of cancer The response to this knowledge of the immune system in cancer has led to a paradigm shift in the management of cancer from conventional therapies such as surgery and radiotherapy to immunotherapy. The goal of immunotherapy is to target only the cancer cells, overcome the immunosuppression induced by a tumor and its microenvironment, and to increase successful response rates by tailoring personalized immunotherapies and predictive biomarkers

44. Therapeutic indications:

45. Targeted cancer therapies :

46. Vaccination therapy : Preventive (or prophylactic ) vaccines Stimulate the production of antibodies that bind to specific targeted cancer –causing viruses and block their ability to cause infection (hepatitis B virus and human papillomavirus)

47. HNSCC: Tumour Antigens and Their Targeting by Immunotherapy

48. Conclusion : Cancer treatment is being revolutionized in the current era due to the success of novel anticancer immunotherapies. Clinically durable responses in oral cancer could be elicited through immunotherapies. The advent of novel technologies and translational research has also revolutionized the immunotherapeutic approach in oral cancer patients. The oral cancer field avidly awaits the clinicians and researchers provision of more insights to maximize the potential of immunotherapies in future endeavors

49. References : Tumor immunology and immunotherapy ( Robert Kress – 5 th edition ) Immunobiology : 11 th edition (Saras ) Tumor immunology : The Glass is half full (review article : 2015 )

50. The host tumor – tumor immune conflict : from immunosuppression to resistance -2017 Tumor antigen presenting cells : changing the rules : cancer immunotherapy -2021 Primer on tumor immunology and cancer immunotherapy : 2018 Cancer immunoediting : form of immunosurveillance to tumor escape Is cancer dangerous to immune cells : 1996( semin )