title: Human papilloma virus load and PD-1/PD-L1, CD8+and FOXP3 in anal cancer patients treated with chemoradiotherapy: Rationale for immunotherapy.
abstract: We examined the prognostic role of immune markers programmed cell death protein-1 (PD-1) and its ligand (PD-L1), CD8+tumor-infiltrating lymphocytes (TILs), FOXP3+ Tregs and phosphorylated Caspase-8 (T273) in patients with anal squamous cell cancer (ASCC) treated with standard chemoradiotherapy (CRT). The baseline immunohistochemical expression of immune markers was correlated with clinicopathologic characteristics, and cumulative incidence of local failure, disease-free survival (DFS) and overall survival (OS) in 150 patients, also in the context of human papilloma virus 16 (HPV16) DNA load and p16INK4aexpression. After a median follow-up of 40 mo (1-205 mo), the 5-y cumulative incidence of local failure and DFS was 19.4% and 67.2%, respectively. Strong immune marker expression was significantly more common in tumors with high HPV16 viral load. In multivariant analysis, high CD8+and PD-1+ TILs expression predicted for improved local control (p= 0.023 andp= 0.007, respectively) and DFS (p= 0.020 andp= 0.014, respectively). Also, high p16INK4a(p= 0.011) and PD-L1 (p= 0.033) expression predicted for better local control, whereas high FOXP3+ Tregs (p= 0.050) and phosphorylated Caspase-8 (p= 0.031) expression correlated with superior DFS. Female sex and high HPV16 viral load correlated with favorable outcome for all three clinical endpoints. The present data provide, for the first time, robust explanation for the favorable clinical outcome of HPV16-positive ASCC patients harboring strong immune cell infiltration. Our findings are relevant for treatment stratification with immune PD-1/PD-L1 checkpoint inhibitors to complement CRT and should be explored in a clinical trial.
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Balermpas
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University , Frankfurt am Main, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Institute of Virology, National Reference Centre for Papilloma- and Polyomaviruses, University of Cologne , Cologne, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wieland
authors.affiliation: Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen , Göttingen, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Rave-Fränk
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany; Department of Gynecology, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Strebhardt
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Fokas
authors.affiliation: Department of Radiotherapy and Oncology, Goethe-University, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK) partner site: Frankfurt/Mainz, Heidelberg, Germany.
authors.forename: Franz
authors.initials: F
authors.lastname: Rödel
keywords: Anal cancer; HPV; PD -1/PD-L1; immune cell infiltration; immunotherapy; prognostic