Characterisation of the protein expression of the emerging immunotherapy targets VISTA, LAG-3 and PRAME in primary uveal melanoma: insights from a southern French patient cohort.

Uveal melanoma (UM) is the most common intraocular tumour in adults, with dismal prognosis once metastases develop, since therapeutic options for the metastatic disease are ineffective. Over the past decade, novel cancer therapies based on immunotherapy have changed the landscape of treatment of different forms of cancer leading to many hopes of improvement in patient overall survival (OS). VISTA, LAG-3 and PRAME are novel promising targets of immunotherapy that have recently gained attention in different solid tumours, but whose relevance in UM remained to be comprehensively evaluated until now. Here, we studied the protein expression of VISTA, LAG-3 and PRAME using immunohistochemistry in representative whole tissue sections from primary UM cases in a cohort of 30 patients from a single centre (Nice University Hospital, Nice, France). The expression of each of these markers was correlated with different clinical and pathological parameters, including onset of metastases and OS. We demonstrated the protein expression of VISTA and LAG-3 in small lymphocytes infiltrating the tumour, while no expression of the proteins was detected in UM cells. For PRAME, nuclear expression was observed in UM cells, but no expression in tumour infiltrating immune cells was identified. Increased levels of VISTA expression in tumour infiltrating lymphocytes (TILs) were associated with nuclear BAP1 expression and better prognosis. Higher levels of LAG-3 in TILs were associated with higher levels of CD8-positive TILs. PRAME nuclear positivity in melanoma cells was associated with epithelioid cell dominant (>90%) UM histological subtype, higher mitotic numbers and a higher percentage of chromosome 8q gain. This study proposes VISTA as a novel relevant immune checkpoint molecule in primary UM and contributes to confirm LAG-3 and PRAME as potentially important immunotherapy targets in the treatment of UM patients, helping to expand the number of immunotherapy candidate molecules that are relevant to modulate in this aggressive cancer.

Prognostic Biomarkers in Uveal Melanoma: The Status Quo, Recent Advances and Future Directions.

Uveal melanoma (UM) is the most common malignant intraocular tumour in the adult population. It is a rare cancer with an incidence of nearly five cases per million inhabitants per year, which develops from the uncontrolled proliferation of melanocytes in the choroid (≈90%), ciliary body (≈6%) or iris (≈4%). Patients initially present either with symptoms like blurred vision or photopsia, or without symptoms, with the tumour being detected in routine eye exams. Over the course of the disease, metastases, which are initially dormant, develop in nearly 50% of patients, preferentially in the liver. Despite decades of intensive research, the only approach proven to mildly control disease spread are early treatments directed to ablate liver metastases, such as surgical excision or chemoembolization. However, most patients have a limited life expectancy once metastases are detected, since there are limited therapeutic approaches for the metastatic disease, including immunotherapy, which unlike in cutaneous melanoma, has been mostly ineffective for UM patients. Therefore, in order to offer the best care possible to these patients, there is an urgent need to find robust models that can accurately predict the prognosis of UM, as well as therapeutic strategies that effectively block and/or limit the spread of the metastatic disease. Here, we initially summarized the current knowledge about UM by compiling the most relevant epidemiological, clinical, pathological and molecular data. Then, we revisited the most important prognostic factors currently used for the evaluation and follow-up of primary UM cases. Afterwards, we addressed emerging prognostic biomarkers in UM, by comprehensively reviewing gene signatures, immunohistochemistry-based markers and proteomic markers resulting from research studies conducted over the past three years. Finally, we discussed the current hurdles in the field and anticipated the future challenges and novel avenues of research in UM.

Current views on tumor mutational burden in patients with non-small cell lung cancer treated by immune checkpoint inhibitors.

In the last few years, the treatment of patients with non-small cell lung cancer (NSCLC) has impressively benefitted from immunotherapy, in particular from the inhibition of immune checkpoints such as programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1). However, despite the significant survival benefit for some patients with advanced NSCLC, the objective response rates (ORRs) remain relatively low no more than 20-30% with a large proportion of patients demonstrating primary resistance. Although the selection of NSCLC patients for the first-line treatment is currently guided by the expression of PD-L1 in tumor cells as detected by immunohistochemistry, this is not the case for the second-line setting. Moreover, the sensitivity and specificity of PD-L1 expression is modest which has prompted the search for additional predictive biomarkers. In this context, the assessment of the tumor mutational burden (TMB), defined as the total number of nonsynonymous mutations in the coding regions of genes, has recently emerged as an additional powerful biomarker to select patients for immunotherapy. The purpose of our review is to highlight the recent advances as well as the challenges and perspectives in the field of TMB and immunotherapy for patients with NSCLC.