title: Density, Distribution, and Composition of Immune Infiltrates Correlate with Survival in Merkel Cell Carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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/mm2) 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; 22(22); 5553-63. ©2016 AACR.
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Laurence
authors.initials: L
authors.lastname: Feldmeyer
authors.affiliation: Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Hudgens
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Genevieve
authors.initials: G
authors.lastname: Ray-Lyons
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Priyadharsini
authors.initials: P
authors.lastname: Nagarajan
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Phyu P
authors.initials: PP
authors.lastname: Aung
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Curry
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.affiliation: Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mino
authors.affiliation: Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez-Canales
authors.affiliation: Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Reuben
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Pei-Ling
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Department of Pathology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Billings
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Bassett
authors.affiliation: Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.affiliation: Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Cooper
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.affiliation: Department of Surgical Oncology The University of Texas MD Anderson Cancer Center, Houston, Texas.|Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas. mtetzlaff@mdanderson.org.|Department of Translational and Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tetzlaff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000957:Antigens, Viral, Tumor / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D015266:Carcinoma, Merkel Cell / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism / Q000473:pathology*; D008297:Male; D059965:Merkel cell polyomavirus / Q000502:physiology; D008875:Middle Aged; D011379:Prognosis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014412:Tumor Virus Infections / Q000378:metabolism / Q000473:pathology
chemical_list: D000957:Antigens, Viral, Tumor; D015415:Biomarkers; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell