Germline HLA and KIR Variation and Disease Control After Immune Checkpoint Blockade in Non-Small Cell Lung Cancer: Exposure Definition Shapes the Signal
5 affiliations
- 1Facultad de Medicina, Universidad de Málaga (UMA), 29071 Málaga, Spain
- 2Servicio de Oncología Médica, Hospital Universitario Virgen de la Victoria, Grupo B-05, Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-Plataforma BIONAND), 29010 Málaga, Spain
- 3Servicio de Oncología Médica, Hospital Regional Universitario de Málaga, Grupo B-05, Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-Plataforma BIONAND), 29010 Málaga, Spain
- 4Estructura Común de Apoyo a la Investigación de Bioinformática, Instituto de Investigación Biomédica de Málaga-Plataforma BIONAND (IBIMA-Plataforma BIONAND), 29590 Málaga, Spain
- 5Precision Cancer Medicine in Lung Cancer–Preclinical, Translational & Clinical Research–Simon Ekman’s Research Group, Department of Oncology-Pathology, Karolinska Institutet, 171 64 Stockholm, Sweden
Abstract
Immune checkpoint inhibitors (ICIs) benefit only a minority of patients with advanced non-small cell lung cancer (NSCLC). Whether germline human leukocyte antigen (HLA) or killer cell immunoglobulin-like receptor (KIR) variation identifies them is unclear, partly because studies define HLA exposures differently. We asked whether allele groups, supertypes and evolutionary divergence associate with disease control. In 122 ICI-treated patients, HLA and KIR typed from germline exomes were tested in 448 pre-specified exposure-endpoint combinations; the primary endpoint was progression or death at 3 months (99 evaluable patients; 31 events). No test survived correction across the screen (lowest n = 0.299). Nominally, HLA-A*02 carriers had higher odds of early failure (odds ratio 4.00, 95% CI 1.64 to 10.07), whereas none of the 12 HLA-B*14 carriers failed (0.07, 0.0006 to 0.58), yet the B27 supertype containing B*14 was null. In 297 public SU2C-MARK patients, B*14 was not supported; A*02 was inconclusive for time to event and not reproduced at a 90-day landmark. HLA-DQA1 divergence at 12 months was hypothesis-generating (within-family n = 0.004). Exome typing resolved HLA allele groups (99.1%) but not KIR (19.0% ambiguous). How an HLA exposure is defined determines whether a signal is visible; only large effects were detectable; replication is required.
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BibTeX
@article{gonzalezhernandez2026germline,
title = {{Germline HLA and KIR Variation and Disease Control After Immune Checkpoint Blockade in Non-Small Cell Lung Cancer: Exposure Definition Shapes the Signal}},
author = {Andrea González-Hernández and Alberto Ríos and Juan Luis Onieva and Alexandra Cantero and Marina Rivero-Aguilar and Guillermo Paz-López and Antonio Rueda-Domínguez and María Garrido-Barros and Beatriz Martínez-Gálvez and Elisabeth Pérez-Ruiz and José Carlos Benítez and Isabel Barragán and Javier Oliver},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = nov,
doi = {10.3390/ijms27219933},
url = {https://www.mdpi.com/1422-0067/27/21/9933},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Germline HLA and KIR Variation and Disease Control After Immune Checkpoint Blockade in Non-Small Cell Lung Cancer: Exposure Definition Shapes the Signal
AU - Andrea González-Hernández
AU - Alberto Ríos
AU - Juan Luis Onieva
AU - Alexandra Cantero
AU - Marina Rivero-Aguilar
AU - Guillermo Paz-López
AU - Antonio Rueda-Domínguez
AU - María Garrido-Barros
AU - Beatriz Martínez-Gálvez
AU - Elisabeth Pérez-Ruiz
AU - José Carlos Benítez
AU - Isabel Barragán
AU - Javier Oliver
PY - 2026
DA - 2026/11/06
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219933
UR - https://www.mdpi.com/1422-0067/27/21/9933
AB - Immune checkpoint inhibitors (ICIs) benefit only a minority of patients with advanced non-small cell lung cancer (NSCLC). Whether germline human leukocyte antigen (HLA) or killer cell immunoglobulin-like receptor (KIR) variation identifies them is unclear, partly because studies define HLA exposures differently. We asked whether allele groups, supertypes and evolutionary divergence associate with disease control. In 122 ICI-treated patients, HLA and KIR typed from germline exomes were tested in 448 pre-specified exposure-endpoint combinations; the primary endpoint was progression or death at 3 months (99 evaluable patients; 31 events). No test survived correction across the screen (lowest n = 0.299). Nominally, HLA-A*02 carriers had higher odds of early failure (odds ratio 4.00, 95% CI 1.64 to 10.07), whereas none of the 12 HLA-B*14 carriers failed (0.07, 0.0006 to 0.58), yet the B27 supertype containing B*14 was null. In 297 public SU2C-MARK patients, B*14 was not supported; A*02 was inconclusive for time to event and not reproduced at a 90-day landmark. HLA-DQA1 divergence at 12 months was hypothesis-generating (within-family n = 0.004). Exome typing resolved HLA allele groups (99.1%) but not KIR (19.0% ambiguous). How an HLA exposure is defined determines whether a signal is visible; only large effects were detectable; replication is required.
SN - 1422-0067
ER -