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KIR Genes and Their Ligands Predict the Response to Anti-EGFR Monoclonal Antibodies in Solid Tumors

Cristina Morales-Estevez1, Juan De la Haba-Rodriguez2, Barbara Manzanares-Martin3

  • 1Medical Oncology Department, IMIBIC, Reina Sofia University Hospital, University of Cordoba , Cordoba , Spain.

Frontiers in Immunology
|December 21, 2016
PubMed

Insights

Specific killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) gene combinations predict better patient response to anti-epidermal growth factor receptor (EGFR) therapies, offering insights into personalized cancer treatment strategies.

Area of Science:

  • Immunogenetics
  • Pharmacogenomics
  • Oncology

Background:

  • Therapeutic monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) are crucial in treating various solid tumors.
  • Patient responses to anti-EGFR therapies exhibit significant variability, suggesting underlying genetic factors.
  • Killer-cell immunoglobulin-like receptors (KIRs) and their human leukocyte antigen (HLA) ligands modulate natural killer cell function, potentially influencing treatment efficacy.

Purpose of the Study:

  • To investigate the association between genetic variability in KIR and HLA genes and patient response to anti-EGFR mAb therapies.
  • To identify specific KIR/HLA genotypes that correlate with improved or diminished treatment outcomes.

Main Methods:

  • Genotyping of 16 KIR gene variants and HLA-B/-C loci in 39 patients treated with anti-EGFR mAbs.
  • Patients were categorized based on time to treatment failure (TTF ≤6 months vs. ≥10 months).
  • KIR genotyping utilized a PCR sequence-specific primer technique; HLA typing employed reverse PCR sequence-specific oligonucleotide methodology.

Main Results:

  • Patients with KIR2DS1/HLA-C2C2-C1C2 combination showed significantly longer TTF (14.76 months) compared to non-carriers (3.73 months, p < 0.001).
  • Patients with KIR3DS1/HLA-Bw4w4-w4w6 combination also demonstrated longer TTF (14.93 months) versus non-carriers (4.6 months, p = 0.005).
  • No other significant associations between KIR/HLA variants and treatment response were observed.

Conclusions:

  • Specific activating KIR/HLA ligand combinations (KIR2DS1/HLA-C and KIR3DS1/HLA-B) are predictive of enhanced patient response to anti-EGFR therapies.
  • These findings contribute to understanding gene polymorphisms influencing anti-EGFR treatment responsiveness in solid tumors.
  • Assessing KIR/HLA gene polymorphisms may be valuable for personalizing cancer medication strategies.
Keywords:
KIR receptorKIR/HLA ligandsadvanced canceranti-EGFRnatural killer cellssolid tumor

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