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. 2025 Aug 20;26(16):8062.
doi: 10.3390/ijms26168062.

Immune Modulation Through KIR-HLA Interactions Influences Cetuximab Efficacy in Colorectal Cancer

María Gómez-Aguilera  1 , Bárbara Manzanares-Martín  2   3 , Arancha Cebrián-Aranda  4 , Antonio Rodríguez-Ariza  1   3   5 , Rafael González-Fernández  2   3 , Laura Del Puerto-Nevado  4 , Jesús García-Foncillas  4 , Enrique Aranda  1   3   5
Affiliations

Immune Modulation Through KIR-HLA Interactions Influences Cetuximab Efficacy in Colorectal Cancer

María Gómez-Aguilera et al. Int J Mol Sci. .

Abstract

Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Cetuximab improves survival by combining EGFR inhibition with immune activation. This study evaluated the influence of killer cell immunoglobulin-like receptor (KIR)-mediated immune responses on cetuximab efficacy in 124 metastatic CRC patients: 55 with wild-type (WT) KRAS and 69 with KRAS mutations. Peripheral blood was genotyped for 19 KIR genes and relevant HLA alleles, focusing on key KIR-HLA interactions (2DL1-C2, 3DL1-Bw4, 3DS1-Bw4). KRAS-WT patients showed better outcomes, receiving more treatment cycles (median: 17 vs. 4) and showing slower disease progression (60% vs. 92.8% at 12 months). WT patients had higher frequencies of inhibitory KIRs and the Bw4 allele, with KIR3DS1-Bw4 heterozygosity linked to longer survival (p = 0.013). In KRAS-mutant patients, heterozygous KIR genotypes (AB) and mixed A/B semi-haplotypes were associated with improved survival (p = 0.002). Multivariate analysis confirmed KIR3DS1-Bw4 as a favorable factor in WT patients and AB genotypes as beneficial in KRAS-mutants. In conclusion, KIR-HLA interactions significantly impact cetuximab efficacy in metastatic CRC, with distinct immunogenetic profiles in WT and KRAS-mutant patients. These results highlight the potential of KIR-HLA profiling to guide personalized treatment strategies.

Keywords: HLA ligands; KIR; anti-EGFR; cetuximab; metastatic colorectal cancer; natural killer cells.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Progression-free survival in KRAS-mutant colorectal cancer patients according to KIR2DL5 status. The presence of KIR2DL5 was associated with longer twelve-month progression-free survival (PFS12) in KRAS-mutant patients treated with cetuximab.
Figure 2
Figure 2
Progression-free survival in KRAS wild-type colorectal cancer patients according to KIR–ligand combinations. (A) The combination of KIR3DS1 with the Bw4 ligand was associated with longer twelve-month progression-free survival (PFS12) in KRAS wild-type (WT) patients treated with cetuximab. (B) Among KRAS-WT patients with KIR3DS1, those who were heterozygous for Bw4 (Bw4Bw6) showed longer PFS12 compared to Bw4 homozygotes (Bw4Bw4) or Bw6 homozygotes (Bw6Bw6).
Figure 3
Figure 3
Survival in KRAS-mutant colorectal cancer patients according to KIR haplotypes. Among KRAS-mutant patients treated with cetuximab, those with heterozygous (AB) KIR haplotypes, comprising one activating (B) and one inhibitory (A) haplotype, demonstrated significantly longer twelve-month progression-free survival (PFS12) compared to homozygous patients (AA or BB).
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