Loss of HLA Class I Expression and T-cell Infiltration or PD-L1 Expression Are Associated with Different Response Patterns to Pembrolizumab in Melanoma.

Background: PD-1 blockade monoclonal antibodies, nivolumab and pembrolizumab, increase quality of life and overall survival of metastatic melanoma and are today’s first-line treatment of metastatic melanoma. Nevertheless, only 40% of the patients will respond to anti-PD-1 monotherapy. In the era of personalized medicine, an important stake is to identify the patients who will benefit from these treatments, which are also responsible for scare but serious side effects. We have tested several biomarkers to discriminate between responders and non-responders. Methods: We have retrospectively analysed 18 patients treated by pembrolizumab for metastatic melanoma. Immunohistochemical staining was performed on pre-treatment metastatic tissue for antigens such as MELANA, TYR, GP100, PD-L1, CD3, CD8, IDO1, HLA class I heavy chain and β2-microglobulin. Two reviewers assessed the staining independently. For PD-L1 testing, the MEL-score was used. For T-cell infiltration, we have quoted the presence of CD3 CD8 T cell and their location. Results: We found that only PD-L1 expression and the presence of T-cell infiltration were associated with a better response to pembrolizumab: PD-L1 expression (p = 0,043), T-cell infiltration (p = 0,025) and T-cell location at the periphery of the tumoral nodules (p = 0,025). PD-L1 expression and the presence of T lymphocytes were also associated with a longer survival. The median overall survival was 31,5 months for the T-cell rich metastasis and PD-L1 high expression versus 4 months for non T-cell infiltrated tumours and 7 months for PD-L1 negative tumours. Furthermore, 50% of the metastases showed reduced or absent HLA class I expression by the tumour cells. The role of tumoral HLA loss in response and resistance to PD-1 blockade has still to be defined. Conclusions: Although significant correlations were observed between some biomarkers and the response to anti-PD-1 therapy as described in larger studies, no predictive biomarker has currently been identified in our small series. Recent and future technical progresses will enable new studies aiming to find reliable biomarkers and to clarify the complex mechanisms of response and resistance to immune checkpoint inhibitors. Legal entity responsible for the study: Cliniques universitaires Saint-Luc. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.