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Background
Response rate of PD-1/PD-L1 immunotherapeutic blockade agents in uveal melanoma (UM) is poor. Lymphocyte activation gene 3 (LAG3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) are the two promising immune checkpoint targets. Therefore, our aim was to explore at how these proteins were expressed in tumour tissue and serum, as well as their prognostic implications in UM.
Methods The expression of LAG3, CTLA-4, CD3, CD4, CD8 and FOXP3 was determined by immunohistochemistry in 54 enucleated UM tissue samples. mRNA expression level of LAG3 and CTLA-4 was determined by quantitative real-time PCR and corroborated by western blotting. Furthermore, soluble form of LAG3, CTLA-4 and CCR8 expression in serum was measured in 40 UM patients using ELISA.
Result The expression of LAG3, CTLA-4, CD3, CD4, CD8 and FOXP3 was observed in 30%, 33%, 41%, 35%, 50% and 39% of the cases, respectively. Loss of nBAP1 expression was significantly correlated with CD8+expression (p=0.012) but not with tumour infiltrating lymphocytes. LAG3 and CTLA-4 mRNA levels were higher in UM compared with normal uveal tissues. Higher LAG3 expression with CD8+expression was associated with lower metastasis-free survival (MFS) (p=0.049), but not with CTLA-4 in UM patients. MFS rate was reduced in patients having lower levels of CCR8 protein (p=0.050) and increased level of LAG3 protein (p=0.001).
Conclusion Our findings suggest that higher levels of LAG3 in UM with histopathologically high-risk parameters predict high metastatic potential and that it could be used as a targeted immunotherapy alone or in combination with PD-1/PD-L1 blockade agents.
- Experimental laboratory
- Immunology
- Pathology
Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.
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Data availability statement
All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.
Footnotes
SK and LS are joint first authors.
MKS and LS contributed equally.
Presented at Presented as a poster presentation at the ESMO Immuno- Oncology Congress 2021 on 8–10 December 2021.
Contributors LS and MKS are responsible for the conception or design of the work; MKS contributes the acquisition, analysis or interpretation of data for the work; SK helps in immunohistochemistry scoring; NK and JJ helps in ELISA experiments; SB Helps in the follow up of the patients; NL and RM provides the tissue samples; SS helps in reviewing the histopathology slides. MKS and LS are the guarantors.
Funding The work was supported by Department for Science and Technology (DST), Govt. of India for providing National Post-Doctoral fellowship (N-PDF) to LS and conducting this research (NPDF/2016/000903).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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