Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma.

Feldmeyer, Laurence; Hudgens, Courtney W; Ray-Lyons, Genevieve; Nagarajan, Priyadharsini; Aung, Phyu P; Curry, Jonathan L; Torres-Cabala, Carlos A; Mino, Barbara; Rodriguez-Canales, Jaime; Reuben, Alexandre; Chen, Pei-Ling; Ko, Jennifer S; Billings, Steven D; Bassett, Roland L; Wistuba, Ignacio I; Cooper, Zachary A; Prieto, Victor G; Wargo, Jennifer A; Tetzlaff, Michael T (2016). Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma. Clinical cancer research, 22(22), pp. 5553-5563. American Association for Cancer Research 10.1158/1078-0432.CCR-16-0392

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PURPOSE

Merkel cell carcinoma (MCC) is an aggressive cancer with frequent metastasis and death with few effective therapies. Because programmed death ligand-1 (PD-L1) is frequently expressed in MCC, immune checkpoint blockade has been leveraged as treatment for metastatic disease. There is therefore a critical need to understand the relationships between MCPyV status, immune profiles, and patient outcomes.

EXPERIMENTAL DESIGN

IHC for CD3, CD8, PD-1, PD-L1, and MCPyV T-antigen (to determine MCPyV status) was performed on 62 primary MCCs with annotated clinical outcomes. Automated image analysis quantified immune cell density (positive cells/mm(2)) at discrete geographic locations (tumor periphery, center, and hotspot). T-cell receptor sequencing (TCRseq) was performed in a subset of MCCs.

RESULTS

No histopathologic variable associated with overall survival (OS) or disease-specific survival (DSS), whereas higher CD3(+) (P = 0.004) and CD8(+) (P = 0.037) T-cell density at the tumor periphery associated with improved OS. Higher CD8(+) T-cell density at the tumor periphery associated with improved DSS (P = 0.049). Stratifying MCCs according to MCPyV status, higher CD3(+) (P = 0.026) and CD8(+) (P = 0.015) T-cell density at the tumor periphery associated with improved OS for MCPyV(+) but not MCPyV(-) MCC. TCRseq revealed clonal overlap among MCPyV(+) samples, suggesting an antigen-specific response against a unifying antigen.

CONCLUSIONS

These findings establish the tumor-associated immune infiltrate at the tumor periphery as a robust prognostic indicator in MCC and provide a mechanistic rationale to further examine whether the immune infiltrate at the tumor periphery is relevant as a biomarker for response in ongoing and future checkpoint inhibitor trials in MCC. Clin Cancer Res; 1-11. ©2016 AACR.

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