HLA-A01 and HLA-B27 Supertypes, but Not HLA Homozygocity, Correlate with Clinical Outcome Among Patients with Non-Small Cell Lung Cancer Treated with Pembrolizumab in Combination with Chemotherapy

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2024 Sep 14

PMID 39272960

Authors

Afaf Abed

Anna Reid

Ngie Law

Michael Millward

Elin S Gray

Affiliations

Soon will be listed here.

Abstract

Introduction: Maximal heterozygosity on the human leukocyte antigen (HLA) loci has been found to be associated with improved survival and development of immune-related adverse events (irAEs) among NSCLC patients treated with immunotherapy. Here, we investigated the effect of germline HLA-I/-II on clinical outcomes among NSCLC patients treated with first-line pembrolizumab in combination with chemotherapy.

Method: We prospectively recruited patients with NSCLC who were commencing first-line pembrolizumab in combination with chemotherapy. DNA from white blood cells was used for high-resolution HLA-I/II typing.

Results: Of the 65 patients recruited, 53 complied with the inclusion criteria. We did not find an association between HLA-I/-II homozygosity and clinical outcome among the studied population. However, the presence of HLA-A01 was associated with unfavourable PFS (HR = 2.32, 95%CI 1.13-4.77, = 0.022) and worsening OS (HR = 2.86, 95%CI 1.06-7.70, = 0.038). The presence of HLA-B27 was associated with improved PFS (HR = 0.35, 95%CI 0.18-0.71, = 0.004) and trends toward improving OS. None of the HLA-I supertypes were associated with the development or worsening of irAEs.

Conclusions: The absence of association between genomic HLA-I/-II homozygosity and clinical outcome among patients with advanced NSCLC treated with pembrolizumab in combination with chemotherapy might reflect a diminished role for HLA molecules among patients with low or no PD-L1. HLA-A01 and HLA-B27 might have a role in predicting clinical outcomes among this cohort of patients. Further studies are needed to explore biomarkers for this group of patients.

References

Sordo-Bahamonde C, Lorenzo-Herrero S, Gonzalez-Rodriguez A, Martinez-Perez A, Rodrigo J, Garcia-Pedrero J . Chemo-Immunotherapy: A New Trend in Cancer Treatment. Cancers (Basel). 2023; 15(11). PMC: 10252089. DOI: 10.3390/cancers15112912. View

Naranbhai V, Viard M, Dean M, Groha S, Braun D, Labaki C . HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study. Lancet Oncol. 2021; 23(1):172-184. PMC: 8742225. DOI: 10.1016/S1470-2045(21)00582-9. View

Thibodeau J, Bourgeois-Daigneault M, Lapointe R . Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy. Oncoimmunology. 2012; 1(6):908-916. PMC: 3489746. DOI: 10.4161/onci.21205. View

Arasanz H, Gato-Canas M, Zuazo M, Ibanez-Vea M, Breckpot K, Kochan G . PD1 signal transduction pathways in T cells. Oncotarget. 2017; 8(31):51936-51945. PMC: 5584302. DOI: 10.18632/oncotarget.17232. View

Neefjes J, Jongsma M, Paul P, Bakke O . Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol. 2011; 11(12):823-36. DOI: 10.1038/nri3084. View

Currenti J, Chopra A, John M, Leary S, McKinnon E, Alves E . Deep sequence analysis of HIV adaptation following vertical transmission reveals the impact of immune pressure on the evolution of HIV. PLoS Pathog. 2019; 15(12):e1008177. PMC: 6924686. DOI: 10.1371/journal.ppat.1008177. View

Ali O, Berner F, Bomze D, Fassler M, Diem S, Cozzio A . Human leukocyte antigen variation is associated with adverse events of checkpoint inhibitors. Eur J Cancer. 2018; 107:8-14. DOI: 10.1016/j.ejca.2018.11.009. View

Sidney J, Peters B, Frahm N, Brander C, Sette A . HLA class I supertypes: a revised and updated classification. BMC Immunol. 2008; 9:1. PMC: 2245908. DOI: 10.1186/1471-2172-9-1. View

Wieczorek M, Abualrous E, Sticht J, Alvaro-Benito M, Stolzenberg S, Noe F . Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation. Front Immunol. 2017; 8:292. PMC: 5355494. DOI: 10.3389/fimmu.2017.00292. View

10.

Salas-Benito D, Perez-Gracia J, Ponz-Sarvise M, Rodriguez-Ruiz M, Martinez-Forero I, Castanon E . Paradigms on Immunotherapy Combinations with Chemotherapy. Cancer Discov. 2021; 11(6):1353-1367. DOI: 10.1158/2159-8290.CD-20-1312. View

11.

Cai W, Zhou D, Wu W, Tan W, Wang J, Zhou C . MHC class II restricted neoantigen peptides predicted by clonal mutation analysis in lung adenocarcinoma patients: implications on prognostic immunological biomarker and vaccine design. BMC Genomics. 2018; 19(1):582. PMC: 6090856. DOI: 10.1186/s12864-018-4958-5. View

12.

Sung H, Ferlay J, Siegel R, Laversanne M, Soerjomataram I, Jemal A . Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021; 71(3):209-249. DOI: 10.3322/caac.21660. View

13.

Principe D, Kamath S, Korc M, Munshi H . The immune modifying effects of chemotherapy and advances in chemo-immunotherapy. Pharmacol Ther. 2022; 236:108111. PMC: 9271143. DOI: 10.1016/j.pharmthera.2022.108111. View

14.

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View

15.

Abed A, Calapre L, Lo J, Correia S, Bowyer S, Chopra A . Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy. J Immunother Cancer. 2020; 8(2). PMC: 7684824. DOI: 10.1136/jitc-2020-001620. View

16.

Garon E, Rizvi N, Hui R, Leighl N, Balmanoukian A, Eder J . Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015; 372(21):2018-28. DOI: 10.1056/NEJMoa1501824. View

17.

Abed A, Law N, Calapre L, Lo J, Bhat V, Bowyer S . Human leucocyte antigen genotype association with the development of immune-related adverse events in patients with non-small cell lung cancer treated with single agent immunotherapy. Eur J Cancer. 2022; 172:98-106. DOI: 10.1016/j.ejca.2022.05.021. View

18.

Hassel J, Piperno-Neumann S, Rutkowski P, Baurain J, Schlaak M, Butler M . Three-Year Overall Survival with Tebentafusp in Metastatic Uveal Melanoma. N Engl J Med. 2023; 389(24):2256-2266. PMC: 11188986. DOI: 10.1056/NEJMoa2304753. View

19.

Negrao M, Lam V, Reuben A, Rubin M, Landry L, Roarty E . PD-L1 Expression, Tumor Mutational Burden, and Cancer Gene Mutations Are Stronger Predictors of Benefit from Immune Checkpoint Blockade than HLA Class I Genotype in Non-Small Cell Lung Cancer. J Thorac Oncol. 2019; 14(6):1021-1031. DOI: 10.1016/j.jtho.2019.02.008. View

20.

Wolf N, Kissiov D, Raulet D . Roles of natural killer cells in immunity to cancer, and applications to immunotherapy. Nat Rev Immunol. 2022; 23(2):90-105. DOI: 10.1038/s41577-022-00732-1. View