Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials

Roberto Moretto, Salvatore Corallo, Antonino Belfiore, Daniele Rossini, Alessandra Boccaccino, Sara Lonardi, Giovanni Centonze, Federica Morano, Marco Maria Germani, Fotios Loupakis, Luca Morelli, Lucio Urbani, Silvia Brich, Federica Marmorino, Michele Prisciandaro, Giuseppe Aprile, Matteo Fassan, Umberto Cillo, Laura Cattaneo, Gabriella FontaniniFilippo De Braud, Alfredo Falcone, Massimo Milione, Filippo Pietrantonio, Chiara Cremolini

Research output: Contribution to journalArticlepeer-review


Background: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. Methods: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. Results: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. Conclusions: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Original languageEnglish
Pages (from-to)78-88
Number of pages11
JournalEuropean Journal of Cancer
Publication statusPublished - Aug 2020


  • Colorectal liver metastasis
  • Immunological parameters
  • Triplet plus targeted agent
  • Tumour microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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