Résumé
An adaptive immune response, is now considered as a favorable prognostic factor in primary colorectal cancer (CRC). It is defined by a dense lymphocytic CD8+/CD45+ infiltrate located within and at the periphery of the tumor. FoxP3+ regulatory T lymphocytes inhibit this adaptive response. However, data about immune response in CRC liver metastases (LM) are lacking, especially after preoperative systemic and targeted treatments, which can modulate the recruitment of immune cells. The aim of our study was to analyze the immune response in CRC LM after different types of pre-operative treatments.
Materials and methods. 107 CRC LM were selected and divided in 4 groups: chemotherapy alone (CT, n= 29), CT + anti-VEGF (bevacizumab) (n= 28), CT + anti-EGFR (cetuximab) (n= 21), surgery alone (control group with no treatment, n= 29). All cases corresponded to LM treated in first-line and to a conventional lieberkuhnian adenocarcinoma. Histologic response was assessed according to Rubbia-Brandt classification, based on the Tumor Regression Grade (TRG). LM were classified as TRG1-2 (major response), TRG3 (partial response) and TRG4-5 (minor or no response). Immune microenvironnement was evaluated in the center (IT, intratumoral) and the periphery (PT, peritumoral) of LM, classified as minor or major and assessed by immunohistochemistry to characterize: i)T lymphocytes: CD8+ (cytotoxic) , CD 45+ (memory), Tbet+ (T helper 1), FoxP3+ (regulators) ii) macrophages: CD68+, CD163+.
Results. A major immune infiltrate was more frequently associated with LM displaying major or partial responses than with LM with no or minor response, with the following markers and locations: CD8+ (PT, IT; p = 0.049, p = 0.004), CD45+ (IT; p = 0.006), Tbet+ (PT; p= 0.015), CD 68+ (IT; p= 0.049), CD163 (PT, IT; p = 0.001, p = 0.022). Conversely, a major FoxP3+ IT immune infiltrate was more frequently associated with LM displaying no or minor response, than with LM showing major or partial responses (p = 0.033). Moreover, a major immune infiltrate was more frequently associated with treated LM than with untreated LM with the following markers and locations: CD8+ (IT; p = 0.014), TBet+ (PT, IT; p = 0.017 p= 0.004), CD 68+ (IT; p = 0.041), CD163+ (IT; p = 0.009). Among treated LM, a major PT CD45+ immune infiltrate was more frequently associated with CT+anti-EGFR than with others treatments (PT; p = 0.016), and a major IT CD45+ immune infiltrate was more frequently associated with CT+anti-EGFR and chemotherapy alone than with CT+anti-VEGF (IT; p = 0.048).
Conclusion. These original data suggest that pre-operative treatments have an impact on CRC LM immune microenvironnement. Indeed, treated LM displaying histologic response are characterized by a CD8+/CD45+ adaptive immune response. Moreover, they simultaneously harbor a stimulated T helper 1 pathway and a down regulation of Treg lymphocytes. Such data suggest immune therapeutic approaches for CRC LM.
Citation Format: Frederic Bibeau, Hugo Gil, Florence Castan, Magalie Pedot, François Quenet, Marc Ychou, Celine Bouquet, Charrier Véronique, Vaios Karanikas, Michael Cannarile, Solange Romagnoli, Fabien Gaire, Florence Boissiere. Impact of preoperative treatments on the immune microenvironnement of colorectal liver metastases. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 141. doi:10.1158/1538-7445.AM2014-141