title: PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis.
abstract: The influence of neoadjuvant radiochemotherapy (RCT) on programmed death-ligand 1 (PD-L1) expression, a predictive marker for programmed cell death protein 1 (PD-1) inhibitor therapy, was studied on tumour and inflammatory cells in rectal adenocarcinoma patients along with its prognostic value.
  
  
  
  PD-L1 immunohistochemistry was performed on tissue microarrays of 103 pre-RCT biopsies and 159 post-RCT surgical specimens (central tumour, invasive front and normal tissue) of 199 patients. In 63 patients, both samples were available. Proportion and maximum intensity of PD-L1-positive (PD-L1+) cells were evaluated.
  
  
  
  RCT increased the proportion of PD-L1-expressing cancer cells from 2.1% to 7.8% in the central tumour (p < 0.001) or 9.3% in the invasive front (p < 0.001). Cancer cell PD-L1 on its own could not predict prognosis. High PD-L1 expression on pre-RCT inflammatory cells (maximum intensity: p = 0.048) and post-RCT invasive front inflammatory cells (p = 0.010) correlated with improved no evidence of disease survival. In multivariate analysis, the combination of low PD-L1 in cancer and inflammatory cells was an independent negative prognostic marker for overall survival (OS) pre-RCT (Cox's proportional hazard ratio 0.438, p = 0.045) and in the invasive front post-RCT (Cox's proportional hazard ratio 0.257, p = 0.030).
  
  
  
  Neoadjuvant RCT is associated with an increased PD-L1 expression in rectal adenocarcinoma patients, which should prompt clinical trials combining radiotherapy and PD-1/PD-L1 pathway blockade. Combined low PD-L1 expression on tumour and inflammatory cells is an independent negative prognostic marker for OS in RCT of rectal adenocarcinoma.
authors.affiliation: Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hecht
authors.affiliation: Department of Nephropathology, Institute of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Maike
authors.initials: M
authors.lastname: Büttner-Herold
authors.affiliation: Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Erlenbach-Wünsch
authors.affiliation: Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Haderlein
authors.affiliation: Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Croner
authors.affiliation: Department of Surgery, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Grützmann
authors.affiliation: Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fietkau
authors.affiliation: Department of Radiation Oncology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany. Electronic address: luitpold.distel@uk-erlangen.de.
authors.forename: Luitpold V
authors.initials: LV
authors.lastname: Distel
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000628:therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059248:Chemoradiotherapy / Q000379:methods; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000627:therapeutic use; D000077150:Oxaliplatin; D011379:Prognosis; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000628:therapy*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D005472:Fluorouracil
keywords: Adenocarcinoma; Cancer; Nivolumab; PD-1; PD-L1; Pembrolizumab; Radiation; Radiochemotherapy; Radiotherapy; Rectal