title: Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases.
abstract: The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Bernatz
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.|Laboratory of Immunology and Vascular Biology, Stanford School of Medicine, Palo Alto, CA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scholz
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.|Department of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Pia S
authors.initials: PS
authors.lastname: Zeiner
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zinke
authors.affiliation: Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kiyose
authors.affiliation: Department of Neuroradiology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Stella
authors.initials: S
authors.lastname: Blasel
authors.affiliation: Department of Neuropathology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beschorner
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neurosurgery, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Senft
authors.affiliation: Department of Neuroradiology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Bender
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ronellenfitsch
authors.affiliation: Department of Tumor biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Harriet
authors.initials: H
authors.lastname: Wikman
authors.affiliation: Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.affiliation: Department of Pathology, University of Dresden, Dresden, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Meinhardt
authors.affiliation: Department of Neurosurgery, Faculty of Medicine and University Hospital Carl Gustav Carus Technische Universität Dresden, Dresden, Germany.
authors.forename: Tareq A
authors.initials: TA
authors.lastname: Juratli
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Senckenberg Institute of Neurooncology, University of Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl H
authors.initials: KH
authors.lastname: Plate
authors.affiliation: Department of Gynecology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Wischhusen
authors.affiliation: Department of Dermatology, University of Tuebingen, Tuebingen, Germany.|Department of Immunology, University of Tuebingen, Tuebingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Edinger Institute, Institute of Neurology, University of Frankfurt am Main, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000556:secondary; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1; PD-L1; brain metastases; tumor-infiltrating lymphocytes