Comment on "Leveraging NGS Data to Refine Immunotherapy Response Prediction in NSCLC: PD-L1 Copy Number, Tumor Mutation Burden, and Beyond".

We appreciate Dr. Inamura for the interest in our work and his comment. We agree with the suggestions that predictive value could be further enhanced by developing models that consider additional NGS-based biomarkers, including tumor mutation burden (TMB), concurrent STK11/KRAS and KEAP1/KRAS mutations, and NOTCH mutations. Along with Dr. Inamura’s commented studies that evaluate TMB, and STK11/KRAS in programmed death-ligand 1 (PD-L1) expression,1Rizvi H. Sanchez-Vega F. La K. et al.Molecular determinants of response to anti-programmed cell death (PD)-1 and anti-programmed death-ligand 1 (PD-L1) blockade in patients with non-small-cell lung cancer profiled with targeted next-generation sequencing.J Clin Oncol. 2018; 36: 633-641Crossref PubMed Scopus (919) Google Scholar, 2Lamberti G. Spurr L.F. Li Y. et al.Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer.Ann Oncol. 2020; 31: 807-814Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 3Ricciuti B. Arbour K.C. Lin J.J. et al.Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status.J Thorac Oncol. 2022; 17: 399-410Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Huang et al.4Huang R.S.P. Murugesan K. Montesion M. et al.Pan-cancer landscape of CD274 (PD-L1) copy number changes in 244 584 patient samples and the correlation with PD-L1 protein expression.J Immunother Cancer. 2021; 9e002680Google Scholar reported that TMB greater than or equal to 10 mutations per megabase was related to CD274 copy number gain in NSCLC and Aujla et al.5Aujla S. Aloe C. Vannitamby A. et al.Programmed death-ligand 1 copy number loss in NSCLC associates with reduced programmed death-ligand 1 tumor staining and a cold immunophenotype.J Thorac Oncol. 2022; 17: 675-687Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar exhibited that STK11 mutation is associated with PD-L1 negativity regardless of KRAS mutant, although KRAS mutation was associated with high PD-L1 expression in STK11 mutant. In addition, they reported that TMB was significantly higher in the PD-L1–high group than PD-L1–low or –negative group.6Schoenfeld A.J. Rizvi H. Bandlamudi C. et al.Clinical and molecular correlates of PD-L1 expression in patients with lung adenocarcinomas.Ann Oncol. 2020; 31: 599-608Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Nevertheless, there is lack of analysis evaluating the integrative prediction model. In addition, recent studies have reported that the deletions of genes located in 9p21 (CDKN2A, CDKN2B, MTAP, and JAK2) were related to the down-regulation of the immune cell recruitment, T-cell activation, clonal expansion, and the up-regulation of immune suppressive pathways, including PD-L1, and associated with worse survival outcomes with immune checkpoint inhibitors (ICIs), compared with the corresponding deletion-negative tumors.7Han G. Yang G. Hao D. et al.9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy.Nat Commun. 2021; 12: 5606Crossref PubMed Scopus (52) Google Scholar, 8Ikeda S. Okamoto T. Okano S. et al.PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer.J Thorac Oncol. 2016; 11: 62-71Abstract Full Text Full Text PDF PubMed Google Scholar, 9Ebot E.M. Duncan D.L. Tolba K. et al.Deletions on 9p21 are associated with worse outcomes after anti-PD-1/PD-L1 monotherapy but not chemoimmunotherapy.NPJ Precis Oncol. 2022; 6: 44Crossref PubMed Scopus (6) Google Scholar Although there is lack of study that investigates the correlation with CD274, we think that the positional proximity with CD274 could synergistically affect the efficacy outcome of ICI. Therefore, we plan for a comprehensive analysis, including the abovementioned mutation profile in our clinic-genomic cohort or other cohorts, if available. Meanwhile, 9p21 loss was reported to be correlated with decreased density of tumor-infiltrating lymphocyte (TIL) and spatial heterogeneity pattern,7Han G. Yang G. Hao D. et al.9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy.Nat Commun. 2021; 12: 5606Crossref PubMed Scopus (52) Google Scholar,10Saltz J. Gupta R. Hou L. et al.Spatial organization and molecular correlation of tumor-infiltrating lymphocytes using deep learning on pathology images.Cell Rep. 2018; 23: 181-193.e7Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar although there is lack of studies that investigate the correlation between deletion of CD274 and TIL. As we have reported the predictive role of TIL for ICI in NSCLC by artificial intelligence–powered spatial analysis, revealing significantly different prognostication, particularly in the PD-L1 expression groups,11Park S. Ock C.Y. Kim H. et al.Artificial intelligence–powered spatial analysis of tumor-infiltrating lymphocytes as complementary biomarker for immune checkpoint inhibition in non–small-cell lung cancer.J Clin Oncol. 2022; 40: 1916-1928Crossref PubMed Scopus (57) Google Scholar we are currently analyzing the correlations between the abovementioned gene mutations, the pattern of TIL, and prognosis after ICI. As suggested by Dr. Inamura, our next work will focus on developing a comprehensive predictive model that incorporates CD274 copy number and immunohistochemistry, TMB, mutational profiles of several genes, and spatial distribution of TIL.8Ikeda S. Okamoto T. Okano S. et al.PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer.J Thorac Oncol. 2016; 11: 62-71Abstract Full Text Full Text PDF PubMed Google Scholar Tae Hee Hong: Conceptualization, Writing—original draft, Writing—review and editing. Yeong Hak Bang: Conceptualization, Writing—original draft, Writing—review and editing. CheolYong Joe: Writing—review and editing. Yoon-La Choi: Conceptualization, Writing—review and editing. Se-Hoon Lee: Conceptualization, Writing—review and editing. Leveraging Next-Generation Sequencing Data to Refine Immunotherapy Response Prediction in NSCLC: Programmed Death-Ligand 1 Copy Number, Tumor Mutation Burden, and BeyondJournal of Thoracic OncologyVol. 18Issue 9PreviewI read the article by Hong et al.,1 published in the Journal of Thoracic Oncology, with great interest. The authors investigated the role of programmed death-ligand 1 (PD-L1; also known as CD274) copy number (CN) alterations, determined by next-generation sequencing (NGS), as a predictive biomarker for response to immune checkpoint inhibitor (ICI) therapy in patients with advanced NSCLC. They reported that PD-L1 CN loss is an independent predictor of the lack of ICI response, complementing the conventional PD-L1 immunohistochemistry (IHC) classification, and that a risk classification system, on the basis of the IHC and CN profiles combined, outperformed the conventional IHC-based system. Full-Text PDF