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

Abstract 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 second ary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan)
or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N Z 59) or cetuximab
(N Z 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 Z 0.002), Human leukocyte antigen (HLA) (p Z 0.003) and Programmed cell
death protein 1 (PD1) (p Z 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 Z 0.003) as compared with others. In addition, patients with high er 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 Z 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.