1. TUMORSKA IMUNOLOGIJA

2. Hanahan D. And Weinberg RA. The hallmarks of cancer
Hanahan D. And Weinberg RA. The hallmarks of cancer. Cell 2000,100:57-70

3. Emerging Hallmarks and Enabling Characteristics An increasing body of research suggests that two additional hallmarks of cancer are involved in the pathogenesis of some and perhaps all cancers. One involves the capability to modify, or reprogram, cellular metabolism in order to most effectively support neoplastic proliferation. The second allows cancer cells to evade immunological destruction, in particular by T and B lymphocytes, macrophages, and natural killer cells. Because neither capability is yet generalized and fully validated,they are labeled as emerging hallmarks. Additionally, two consequential characteristics of neoplasia facilitate acquisition of both core and emerging hallmarks. Genomic instability and thus mutability endow cancer cells with genetic alterations that drive tumor progression. Inflammation by innate immune cells designed to fight infections
and heal wounds can instead result in their inadvertent support of multiple hallmark capabilities, thereby manifesting the now widely appreciated tumor-promoting consequences of inflammatory responses.
Hanahan D. And Weinberg RA. The hallmarks of cancer. The next generation. Cell, 2011, 164: 3

4. SADRŽAJ IMUNSKI NADZOR TUMORSKI ANTIGENI
EFEKTORSKI MEHANIZMI ANTITUMORSKE IMUNOSTI
MEHANIZMI IZBEGAVANJA IMUNSKOG ODGOVORA
IMUNOTERAPIJA TUMORA

5. TRI ULOGE IMUNSKOG SISTEMA U PREVENCIJI TUMORA
Eliminacija ili supresija virusnih infekcija (prevencija virusom indukovanih tumora)
Efikasna eliminacija patogena i brzo okončavanje inflamacije (onemogućavanje tumorigeneze)
Identifikacija i eliminacija tumorskih ćelija kao rezultat prepoznavanja tumorskih antigena (imunski nadzor)

6. IMUNSKI NADZOR
Fiziološka funkcija imunskog sistema da prepozna i uništi transformisane ćelije pre nego što nastane tumor i da ubija ćelije tumora kada se već razvio.

11. The immune status of mice is a critical determinant of their susceptibility to tumors induced by
chemical carcinogens. Over the past two decades, numerous studies have established that immunodeficient
mice are more tumor prone than are immunocompetent mice after treatment with carcinogens
such as MCA. The immunodeficient mice tested in such experiments include gene-targeted mice
on pure genetic backgrounds with deficits of innate or adaptive immunity as well as wild-type mice
rendered immunodeficient by chronic administration of monoclonal antibodies that, for example, deplete
CD4+ and CD8+ T cells or interferon-g. Immunodeficiency has also been found to increase the susceptibility
of untreated mice to spontaneously arising tumors and to increase the incidence of tumor
formation in mouse genetic models of cancer. 11

12. Figure 14-12 TUMORSKI ANTIGENI Mutacija Normalna ćelija
Tumorska ćelija

13. Figure 14-13 TUMORSKI ANTIGENI Reaktivacija gena
Normalna ćelija
Reaktivacija gena
Preterana ekspresija gena
Tumorska ćelija
Tumorska ćelija

14. TUMORSKI ANTIGENI Tumor-specifični antigeni (TSA)
Tumor-asocirani antigeni (TAA)

18. EFEKTORSKI MEHANIZMI ANTITUMORSKOG ODGOVORA
T limfociti
NK ćelije
Antitela
Makrofagi

19. EFEKTORSKI MEHANIZMI ANTITUMORSKOG ODGOVORA
T limfociti
NK ćelije
Antitela
Makrofagi

25. EFEKTORSKI MEHANIZMI ANTITUMORSKOG ODGOVORA
T limfociti
NK ćelije
Antitela
Makrofagi

26. Figure 1-6

27. Prepoznavanje zaraženih i tumorskih ćelija

29. EFEKTORSKI MEHANIZMI ANTITUMORSKOG ODGOVORA
T limfociti
NK ćelije
Antitela
Makrofagi

30. Antibody-dependent cell cytotoxicity (ADCC) is initiated by the recognition of IgG-coated tumours by Fc receptors for IgG FcγRs, which are expressed by effector immune cells such as natural killer (NK) cells, macrophages, and neutrophils. These interactions lead to ADCC and tumour cell apoptosis, which is mediated by the delivery of perforin and granzymes to the tumour cell. b | The IgG-coated apoptotic tumour cells can bind Fc receptors on phagocytes and initiate Fc-dependent phagocytosis, leading to the lysosomal degradation of the tumour cell. c | Peptides derived from lysosomal degradation of tumour cells can be loaded on to MHC class II molecules, leading to the activation of CD4+ helper T cells. In addition to CD4+ T cell activation, dendritic cells can cross-present tumour cell antigens and prime cytotoxic CD8+ T cells. TCR, T cell receptor. 30 30

31. EFEKTORSKI MEHANIZMI ANTITUMORSKOG ODGOVORA
T limfociti
NK ćelije
Antitela
Makrofagi

32. Ubijanje ćelija tumora
ROS, NO, lizozomalni enzimi, citokini (TNFα)

34. Imunski odgovor na tumor je moguć
ALI
nije adekvatno pokrenut/aktivisan
suvuše je slab
ne traje dovoljno dugo da spreči rast tumora

35. MEHANIZMI KOJIM TUMOR IZBEGAVA IMUNSKI ODGOVOR
Smanjena ekspresija MHC molekula
Neadekvatna prezentacija tumorskih antigena
Selekcija mutiranih tumorskih ćelija
Antigenska modulacija
Maskiranje antigena
Supresija imunskog odgovora
Produkcija imunosupresivnih proteina
Indukcija regulatornih ćelija

38. IMUNOTERAPIJA TUMORA Nespecifična Specifična Pasivna Aktivna
monoklonska antitela
adoptivna (LAK, TIL)
Aktivna
Vakcinacija

39. Monoklonska antitela
Uništavaju tumor aktivacijom komplementa ili posredstvom NK ćelija (ADCC)
Indukuju imunski odgovor na tumor (anti CTLA4, PD1)
Blokiraju receptorski protein uključen u nastanak ili progresiju tumora (EGFR, VEGF)
Vezani za izotop, toksin ili siRNA specifično ubijaju tumor

40. Figure 14-17

44. Adoptivna ćelijska imunoterapija

45. Tumours are often complex masses containing diverse cell types
Tumours are often complex masses containing diverse cell types. These masses can be surgically resected and fragmented, and the cells can be placed in wells into which a T cell growth factor, such as interleukin-2 (IL-2), is added. T cell populations that have the desired T cell receptor (TCR) specificity can be selected and expanded, and then adoptively transferred into patients with cancer. Prior to this adoptive transfer, hosts can be immunodepleted by either chemotherapy alone or chemotherapy in combination with total-body irradiation. The combination of a lymphodepleting preparative regimen, adoptive cell transfer and a T cell growth factor (such as IL-2) can lead to prolonged tumour eradication in patients with metastatic melanoma. MDSC, myeloid-derived suppressor cell; NK, natural killer; TReg, regulatory T. 46

46. VAŽNO ZA PRAVLJENJE VAKCINE PROTIV TUMORA
Identifikovati tumorske antigene
Stimulisati efikasan imunski odgovor protiv tumora
Izbeći autoimunsko oštećenje