The histological growth patterns in liver metastases from colorectal cancer display differences in lymphoid, myeloid, and mesenchymal cells

Abstract

Desmoplasia; Hepatic metastases; Histologic growth pattern

Desmoplàsia; Metàstasis hepàtiques; Patró de creixement histològic

Desmoplasia; Metástasis hepáticas; Patrón de crecimiento histológico

Colorectal liver metastases grow following different histologic growth patterns (HGPs), classified as desmoplastic and nondesmoplastic (dHGP, non-dHGP), being the latter associated with worst prognosis. This study aimed to investigate the tumor microenvironment (TME) between HGPs supporting different survival. Multiplexed immunohistochemical staining was performed with the Opal7 system in a 100-patients cohort to evaluate the tumor–liver interface with three different cell panels: lymphoid, myeloid, and carcinoma-associated fibroblasts. Differences between HGPs were assessed by Mann–Whitney U test with Pratt correction and Holm–Bonferroni multitest adjustment. Cytotoxic T-cells were more abundant in tumoral areas of dHGP, while non-dHGP had higher macrophages infiltration, Th2, CD163+, and Calprotectin+ cells as well as higher pSMAD2 expression. Regarding carcinoma-associated fibroblasts, several subsets expressing COL1A1 were enriched in dHGP, while αSMAlow_single cells were present at higher densities in non-dHGP. Interestingly, Calprotectin+ cells confer better prognoses in non-dHGP, identifying a subgroup of good outcome patients that unexpectedly also show an enrichment in other myeloid cells. In summary, our results illustrate different TME landscapes with respect to HGPs. dHGP presents a higher degree of immunocompetence, higher amounts of Collagen 1 as well as lesser presence of myeloid cell populations, features that might be influencing on the better prognosis of encapsulated metastases.

This work has been supported by grant PI18/1140 from the Fondo de Investigaciones Sanitarias of the Spanish Government (grantPI18/1140), Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”/“A way of shaping Europe” and AGAUR grant number SGR771 and 2019FI_B00673. A. M. was supported by grant from the Swedish Cancer Society to (CAN 2017/1066), Selanders Foundation and P.O. Zetterling Foundation. In addition, G. G. V. is recipient of the 2019 FI_B 00673 grant, funded by AGAUR the Department of Health of the Generalitat de Catalunya by the call “Ajuts per a la contractació de personal investigador novell FI 2019.” We thank CERCA Programme/Generalitat de Catalunya for institutional support.