engleski

REGULATION OF PD-1/PD-L1 PATHWAY IN MALIGNANT MELANOMA – A PILOT STUDY

BACKROUND: Malignant melanoma (MM) is one of the genetically most complex tumors. In modern oncology, emphasis is on immunotherapy and targeted mutation-dependent therapy. It is known that MM craftily avoiding the immune response of the host. Inhibitory molecules on the surface of malignant cells block the cytotoxic effect of T lymphocytes. Lymphocytes in tumor inflammatory cell infiltrate (TIL) show PD-1 (programmed cell death 1) protein expression. Known ligands for PD- 1 are PD-L1 and PD-L2. The extrinsic and intrinsic mechanisms of PD-L1 regulation in melanoma require further research because it's crucial for advancement in this type of melanoma patient therapy. AIM: In order to predict the efficacy and optimization of anti-PD-1 and anti-PD-L1 therapy, alone or in combination with other treatment options, it's important to clarify regulation mechanisms. Our project research is based on role of several types of regulation on PD-1 / PD-L1 signal pathway control proteins. We divided them into three groups: changes in genetic material and signal pathways of melanoma cell, regulation by the immune system, and regulation by tumor- microenvironment enzymes. In this pilot study, we will analyse a small group of patients and examine regulation by the immune system. METHODS: Retrospectively, archive material in basis of the Department of Pathology, Faculty of Medicine in Rijeka, will be used in this research. Primary malignant melanoma biopsies specimens of patients treated with pembrolizumab immunotherapy in Clinic for Radiotherapy and Oncology, Clinical Hospital Centre Rijeka, will be analysed. Preparation and immunohistochemical staining will follow with the determination of PD-L1 immunohistochemical positivity, and presence of CD3+ and CD20+ lymphocytes. Primary melanomas centrally will be reviewed for TIL grade (absent, non-BRISK, or BRISK). The odds of TIL grades associated with clinicopathologic features and melanoma cell PD-L1 expression will be examined. RESULTS: Since March 2017, a total of 31 patients with metastatic melanoma have been treated with pembrolizumab at our Clinic. In this pilot study, we included some of patients who received at least 3 cycles of pembrolizumab (every 3 weeks). They were divided into two groups: Group 1 (n=6) consisted of patients who received more than 6 cycles of therapy (median of cycles in this group was 19) without signs of disease progression, and Group 2 (n=4) consisted of patients who at the first radiological control (after 5 cycles) had signs of disease progression according to RECIST criteria. Analysis of biopsies of primary melanomas in Group 1 showed that all samples had BRISK type TIL (3 BRISK A and 3 BRISK B). In contrast, in Group 2 we found 1 BRISK B, 2 non- BRISK and 1 absent tumor infiltrating lymphocytes. PD-L1 expression did not statistically significantly correlate with TIL type in either group. CONCLUSION: Definition of proteins responsible for immune inhibition and immune cell regulation will contribute to better use of immunotherapy as treatment for metastatic melanoma and possible future use of same treatment in adjuvant therapy. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

Malignant melanoma ; Immunotherapy ; Programmed cell death 1 Receptor ; Tumor inflammatory cell infiltrate

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