title: Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy.
abstract: Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC.
authors.affiliation: Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Sara
authors.initials: S
authors.lastname: Michel
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Inka
authors.initials: I
authors.lastname: Zoernig
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.forename: Anna
authors.initials: A
authors.lastname: Spille
authors.forename: Thora
authors.initials: T
authors.lastname: Pommerencke
authors.forename: Doeberitz Magnus
authors.initials: DM
authors.lastname: von Knebel
authors.forename: Gunnar
authors.initials: G
authors.lastname: Folprecht
authors.forename: Birgit
authors.initials: B
authors.lastname: Luber
authors.forename: Nadine
authors.initials: N
authors.lastname: Feyen
authors.forename: Uwe M
authors.initials: UM
authors.lastname: Martens
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Esther
authors.initials: E
authors.lastname: Herpel
authors.forename: Juergen
authors.initials: J
authors.lastname: Weitz
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
mesh_terms: D002452:Cell Count; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018572:Disease-Free Survival; D006801:Humans; D008113:Liver Neoplasms / Q000556:secondary*; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D009362:Neoplasm Metastasis; D011379:Prognosis