Role of the PD-1 and PD-L1 signal pathways in the suppression of the T-cell immune response in solid tumor progression

Abstract

Rak je izrazit javnozdravstveni problem u Republici Hrvatskoj i drugi je uzrok smrti, nakon bolesti srca i krvnih žila. Solidni tumori čine velik postotak mortaliteta i morbiditeta raka te je starenjem stanovništva primijećeno povećanje incidencije. Terapija solidnih tumora je izrazito kompleksan predmet istraživanja, a novije spoznaje nam omogućuju pronalaženje novih meta i postupaka terapije. Nedavna su istraživanja pokazala kako solidni tumori uređuju imunološki odgovor te onemogućuju imunološki napad u tumorskom mikrookolišu, u procesu koji se opisuje kao tumorski bijeg. Jedna od ključnih komponenti u tumorskom bijegu o imunološkog sustava je PD-1 molekula koju nalazimo na površini aktiviranih T limfocita i koja dolazi u interakciju s PD-L1 i PD-L2. Tumorske stanice, ali i nekolicina drugih staničnih tipova, izražavaju PD-L1 na svojoj površini i tako dokidaju napad citotoksičnih T limfocita. Blokadom te inhibicije iscrpljeni T limfociti koji nastanjuju tumorski mikrookoliš ponovno poprimaju efektorski fenotip i pokreću obnovljeni napad na neoplastične stanice. Imunoterapija koja se bazira na blokadi PD-1/PD-L1 signalne osi pokazala je znatan potencijal u kliničkim istraživanjima. U Republici Hrvatskoj upravo je taj vid imunoterapije ušao u kliničku praksu u slučaju nekolicine solidnih tumora, primarno melanoma, trostruko negativnog karcinoma dojke, ne-sitnostaničnog karcinoma pluća, karcinoma mokraćnog mjehura te karcinoma bubrežnih stanica. U ovom diplomskom radu obrađeni su detalji vezani uz djelovanje osi PD-1/PD-L1 na imunološko uređivanje tumora i kliničke implikacije njene blokade.Cancer poses a major public health problem in the Republic of Croatia and it is the second leading cause of death, after cardiovascular disease. Solid tumours account for a large percentage of cancer mortality and morbidity, and an increased incidence has been observed as the population ages. Therapy of solid tumours is an extremely complex subject of research, and recent findings allow us to find new targets and procedures for therapy. Recent research has shown that solid tumours regulate the immune response and prevent an immune attack in the tumour microenvironment, in a process described as cancer immune escape. One of the key components in the tumour escape of the immune system is the PD-1 molecule found on the surface of activated T lymphocytes, which interacts with PD-L1 and PD-L2. Tumour cells, but also several other cell types, express PD-L1 on their surface and thus eliminate the attack of cytotoxic T lymphocytes. By blocking this inhibition, exhausted T lymphocytes that inhabit the tumour microenvironment regain the effector phenotype and commence a renewed attack on neoplastic cells. Immunotherapy based on the blockade of the PD-1/PD-L1 signalling axis has shown significant potential in clinical trials. In the Republic of Croatia, this type of immunotherapy has entered clinical practice in the case of several solid tumours, primarily melanoma, triple-negative breast cancer, non-small cell lung cancer, bladder cancer and renal cell carcinoma. In this thesis, the details related to the effect of the PD-1/PD-L1 axis on the immunoediting of the tumour and the clinical implications of its blockade are discussed