CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

Abstract

Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient's subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy's sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07-10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17-18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8-12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.

Figure 1

Progression Free Survival: The median PFS was not reached in CDX-2-positive patients (dotted/green line) versus 2.07 months (95%CI 2.07–10.8) in CDX2-negative patients (continuous/blue line) (p = 0.0011) The proportion of patients without disease progression at 12 months was 81% in the CDX-2-positive group. All the two CDX-2-negative patients had discontinued treatment due to disease progression.

Figure 2

Overall Survival: Median Overall Survival was not reached in CDX-2-positive patients (dotted/green line) versus 2.17 months (95%CI 2.17–18.7) in CDX-2-negative patients (continuous/blue line) (p = 0.026).

Figure 3

The relationship between CDX-2 expression and immunotherapy response: CDX-2 interacts with histone acetyltransferase p300. The CDX-2/p300 complex activates the enhancer of CXCL14 to promote its expression. Lack of expression of the CDX2/CXCL14 axis reduces the recruitment of immune cells to the microenvironment, inhibiting the therapeutic efficacy of natural killer cell-mediated cancer immunotherapy.