CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients

Crescenzo D'Alterio, Guglielmo Nasti, M. Polimeno, Alessandro Ottaiano, Manuel Conson, Luisa Circelli, Giovanni Botti, Giosuè Scognamiglio, Sara Santagata, Chiara De Divitiis, Anna Nappi, Maria Napolitano, Fabiana Tatangelo, Roberto Pacelli, Francesco Izzo, Emilia Vuttariello, Gerardo Botti, Stefania Scala

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Abstract

A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases (CRLM). At a median follow up of 28 months, 20/33 patients were dead of disease, 8 were alive with disease and 5 were alive with no evidence of disease. To shed further insight into biological features accounting for different outcomes, the expression of CXCR4–CXCL12–CXCR7, TLR2–TLR4, and the programmed death receptor-1 (PD-1)/programmed death-1 ligand (PD-L1) was evaluated in excised liver metastases. Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients. CXCR4 and CXCR7, TLR2/TLR4, and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues. CXCR4 protein was negative/low in 10/31, and high in 21/31, CXCR7 was negative/low in 16/31 and high in 15/31, CXCL12 was negative/low in 14/31 and high in 17/31 CRLM. PD-1 was negative in 19/30 and positive in 11/30, PD-L1 was negative/low in 24/30 and high in 6/30 CRLM. Stromal PD-L1 expression, affected the progression-free survival (PFS) in the CRLM population. Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival (CSS) (p = 0.001 and p = 0.0008); in these patients, KRAS mutation identified a subgroup with a significantly worse CSS (p < 0.01). Thus, CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients. Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group. Thus, CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs.

Original languageEnglish
Article numbere1254313
JournalOncoImmunology
Volume5
Issue number12
DOIs
Publication statusPublished - Dec 1 2016

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Death Domain Receptors
Liver Neoplasms
Colorectal Neoplasms
Neoplasm Metastasis
Disease-Free Survival
Liver
Survival
Neoplasms
Clinical Trials
Ligands
Messenger RNA
Mutation

Keywords

  • colorectal cancer liver metastases (CRLM)
  • CXCR4–CXCL12–CXCR7 axis
  • KRAS mutation
  • PD-1/PD-L1
  • toll-like receptors (TLRs)

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients. / D'Alterio, Crescenzo; Nasti, Guglielmo; Polimeno, M.; Ottaiano, Alessandro; Conson, Manuel; Circelli, Luisa; Botti, Giovanni; Scognamiglio, Giosuè; Santagata, Sara; De Divitiis, Chiara; Nappi, Anna; Napolitano, Maria; Tatangelo, Fabiana; Pacelli, Roberto; Izzo, Francesco; Vuttariello, Emilia; Botti, Gerardo; Scala, Stefania.

In: OncoImmunology, Vol. 5, No. 12, e1254313, 01.12.2016.

Research output: Contribution to journalArticle

D'Alterio, Crescenzo ; Nasti, Guglielmo ; Polimeno, M. ; Ottaiano, Alessandro ; Conson, Manuel ; Circelli, Luisa ; Botti, Giovanni ; Scognamiglio, Giosuè ; Santagata, Sara ; De Divitiis, Chiara ; Nappi, Anna ; Napolitano, Maria ; Tatangelo, Fabiana ; Pacelli, Roberto ; Izzo, Francesco ; Vuttariello, Emilia ; Botti, Gerardo ; Scala, Stefania. / CXCR4–CXCL12–CXCR7, TLR2–TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients. In: OncoImmunology. 2016 ; Vol. 5, No. 12.
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AU - Polimeno, M.

AU - Ottaiano, Alessandro

AU - Conson, Manuel

AU - Circelli, Luisa

AU - Botti, Giovanni

AU - Scognamiglio, Giosuè

AU - Santagata, Sara

AU - De Divitiis, Chiara

AU - Nappi, Anna

AU - Napolitano, Maria

AU - Tatangelo, Fabiana

AU - Pacelli, Roberto

AU - Izzo, Francesco

AU - Vuttariello, Emilia

AU - Botti, Gerardo

AU - Scala, Stefania

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