title: CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients.
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 andp= 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.
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Crescenzo
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Guglielmo
authors.initials: G
authors.lastname: Nasti
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Marianeve
authors.initials: M
authors.lastname: Polimeno
authors.affiliation: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ottaiano
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy.
authors.forename: Manuel
authors.initials: M
authors.lastname: Conson
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Circelli
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Botti
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Giosuè
authors.initials: G
authors.lastname: Scognamiglio
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Santagata
authors.affiliation: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Divitiis
authors.affiliation: Gastrointestinal Medical Oncology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Nappi
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Napolitano
authors.affiliation: Pathology Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Tatangelo
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Pacelli
authors.affiliation: Hepatobiliary Surgery Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Izzo
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Emilia
authors.initials: E
authors.lastname: Vuttariello
authors.affiliation: Department of Advanced Biomedical Sciences, Federico II University School of Medicine , Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.affiliation: Functional Genomics Unit, Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione Giovanni Pascale" - IRCCS , Napoli, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
keywords: CXCR4–CXCL12–CXCR7 axis; KRAS mutation; PD-1/PD-L1; colorectal cancer liver metastases (CRLM); toll-like receptors (TLRs)