Abstract

Background: Merkel Cell Carcinoma (MCC) is an aggressive cutaneous malignancy with a dismal prognosis known to repress MHC-I. Anti-PD-1/PD-L1 checkpoint inhibitors have produced objective responses in ~50% of patients, and are now standard of care. Given these recent successes, identification of other targetable immune checkpoints in the MCC tumor microenvironment (TME) in combination with anti-PD-1 is of great interest. Additionally, gamma-delta (γδ) T cells may play critical roles in the response to MHC-I deficient cancers; therefore, evaluating γδ-T cells as a prognostic biomarker is warranted.  Methods: Here, we characterized the expression of PDL1, PD1, CD3, LAG3, MHC-I, and γδ-T cells by IHC in 56 cases of non-immunotherapy-treated MCC, and quantified expression levels and marker density via HALO. Results: Increased density of LAG3 and γδ-T cells correlated with other markers of an inflamed TME, with significant positive associations across all six markers (p<.002). Reflective of their putative role in the response to MHC-I suppressed cancers, cases with low HLA-I density showed a trend towards a higher ratio of γδ-T cells:CD3 (Spearman's r=-0.1582, p=0.21). Importantly, compared to CD3 density, which was associated with non-significantly improved progression free survival (HR=0.69, p=0.36, log-rank), both LAG3 density (HR=0.49, p=.09, log-rank) and γδ-T cell density (HR=0.31, p=0.01, log-rank) showed improved biomarker performance.   Conclusions: LAG3 is expressed in MCC infiltrates and is prognostic in pretreatment MCC, suggesting a potential role for LAG3 inhibition in MCC. Additionally, these data suggest that γδ-T cells may play a critical role in the response to MCC and γδ-T cell density may represent a novel biomarker in MCC.