Inducible T cell costimulator ligand (ICOSLG) regulates T cell functional states, yet its role in small cell lung cancer (SCLC) remains poorly characterized. By integrating multiple cohorts, we found that high tumor-intrinsic ICOSLG was associated with poor overall survival (OS) in the TU-SCLC cohort (p = 0.010) and the Wang et al. cohort (p < 0.001), and was associated with inferior efficacy to chemo-immunotherapy (hazard ratio [HR] = 2.66, p = 0.008). Consistently, the ICOSLG high subgroup exhibited significantly reduced functional CD8+ T cell infiltration, elevated exhausted CD8+ T cells, decreased effector molecules such as GZMK and IFNG, and enrichment of malignant pathways, including hypoxia, epithelial–mesenchymal transition, and others. Meanwhile, the correlation between ICOSLG and NEUROD1 expression was observed. On the contrary the subgroup high in ICOS, the main ICOSLG receptor, harbored NOTCH pathway mutations, showed an inflamed tumor microenvironment, better prognosis, and prolonged OS with chemo-immunotherapy (HR = 0.52, p = 0.003). Dual ICOSLG and ICOS stratification revealed that the ICOSLG low and ICOS high subgroup derived the greatest benefit from chemo-immunotherapy (median OS: 17.2 vs. 9.8 months; p < 0.001). Collectively, this dual-stratification strategy refined patient selection for chemo-immunotherapy, unveiled actionable targets, and ultimately advanced precision immunotherapy in SCLC.
| [1] |
Y. Zhang, S. Vaccarella, E. Morgan, et al., “Global Variations in Lung Cancer Incidence by Histological Subtype in 2020: A Population-based Study,” The Lancet Oncology 24, no. 11 (2023): 1206–1218.
|
| [2] |
A. F. Gazdar, P. A. Bunn, and J. D. Minna, “Small-cell Lung Cancer: What We Know, What We Need to Know and the Path Forward,” Nature Reviews Cancer 17, no. 12 (2017): 725–737.
|
| [3] |
S. Wang, J. Tang, T. Sun, et al., “Survival Changes in Patients With Small Cell Lung Cancer and Disparities Between Different Sexes, Socioeconomic Statuses and Ages,” Scientific Reports 7, no. 1 (2017): 1339.
|
| [4] |
L. Horn, A. S. Mansfield, A. Szczesna, et al., “First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer,” New England Journal of Medicine 379, no. 23 (2018): 2220–2229.
|
| [5] |
J. W. Goldman, M. Dvorkin, Y. Chen, et al., “Durvalumab, With or Without tremelimumab, plus Platinum-etoposide versus Platinum-etoposide Alone in First-line Treatment of Extensive-stage Small-cell Lung Cancer (CASPIAN): Updated Results From a Randomised, Controlled, Open-label, Phase 3 Trial,” The Lancet Oncology 22, no. 1 (2021): 51–65.
|
| [6] |
J. Wang, C. Zhou, W. Yao, et al., “Adebrelimab or Placebo plus Carboplatin and Etoposide as First-line Treatment for Extensive-stage Small-cell Lung Cancer (CAPSTONE-1): A Multicentre, Randomised, Double-blind, Placebo-controlled, Phase 3 Trial,” The Lancet Oncology 23, no. 6 (2022): 739–747.
|
| [7] |
Y. Cheng, L. Han, L. Wu, et al., “Effect of First-Line Serplulimab vs Placebo Added to Chemotherapy on Survival in Patients with Extensive-Stage Small Cell Lung Cancer: The ASTRUM-005 Randomized Clinical Trial,” Jama 328, no. 12 (2022): 1223–1232.
|
| [8] |
S. Khayyamian, A. Hutloff, K. Buchner, et al., “ICOS-ligand, Expressed on human Endothelial Cells, Costimulates Th1 and Th2 Cytokine Secretion by Memory CD4+ T Cells,” Proceedings of the National Academy of Sciences of the United States of America 99, no. 9 (2002): 6198–6203.
|
| [9] |
R. Iwata, J. Hyoung Lee, M. Hayashi, et al., “ICOSLG-mediated Regulatory T-cell Expansion and IL-10 Production Promote Progression of Glioblastoma,” Neuro-oncol 22, no. 3 (2020): 333–344.
|
| [10] |
Y. Lu, Q. Zhao, J. Y. Liao, et al., “Complement Signals Determine Opposite Effects of B Cells in Chemotherapy-Induced Immunity,” Cell 180, no. 6 (2020): 1081–1097 e24.
|
| [11] |
J. Lv, Y. Wei, J. H. Yin, et al., “The Tumor Immune Microenvironment of Nasopharyngeal Carcinoma After Gemcitabine plus Cisplatin Treatment,” Nature Medicine 29, no. 6 (2023): 1424–1436.
|
| [12] |
S. A. Abdel-Rahman, K. Swiderek, and M. T. Gabr, “First-in-class Small Molecule Inhibitors of ICOS/ICOSL Interaction as a Novel Class of Immunomodulators,” RSC Medicinal Chemistry 14, no. 9 (2023): 1767–1777.
|
| [13] |
D. Raineri, C. Dianzani, G. Cappellano, et al., “Osteopontin Binds ICOSL Promoting Tumor Metastasis,” Communications Biology 3, no. 1 (2020): 615.
|
| [14] |
Q. Liu, J. Zhang, C. Guo, et al., “Proteogenomic Characterization of Small Cell Lung Cancer Identifies Biological Insights and Subtype-specific Therapeutic Strategies,” Cell 187, no. 1 (2024): 184–203 e28.
|
| [15] |
A. S. Mansfield, A. Kazarnowicz, N. Karaseva, et al., “Safety and Patient-reported Outcomes of Atezolizumab, Carboplatin, and Etoposide in Extensive-stage Small-cell Lung Cancer (IMpower133): A Randomized Phase I/III Trial,” Annals of Oncology 31, no. 2 (2020): 310–317.
|
| [16] |
S. V. Liu, M. Reck, A. S. Mansfield, et al., “Updated Overall Survival and PD-L1 Subgroup Analysis of Patients with Extensive-Stage Small-Cell Lung Cancer Treated with Atezolizumab, Carboplatin, and Etoposide (IMpower133),” Journal of Clinical Oncology 39, no. 6 (2021): 619–630.
|
| [17] |
A. Bardia, S. M. Tolaney, K. Punie, et al., “Biomarker Analyses in the Phase III ASCENT Study of Sacituzumab Govitecan versus Chemotherapy in Patients With Metastatic Triple-negative Breast Cancer,” Annals of Oncology 32, no. 9 (2021): 1148–1156.
|
| [18] |
Z. Huo, Y. Duan, D. Zhan, et al., “Proteomic Stratification of Prognosis and Treatment Options for Small Cell Lung Cancer,” Genomics, Proteomics & Bioinformatics 22, no. 2 (2024): qzae033.
|
| [19] |
W. H. Fridman, L. Zitvogel, C. Sautes-Fridman, and G. Kroemer, “The Immune Contexture in Cancer Prognosis and Treatment,” Nature Reviews Clinical Oncology 14, no. 12 (2017): 717–734.
|
| [20] |
F. Balkwill and A. Mantovani, “Inflammation and Cancer: Back to Virchow?,” Lancet 357, no. 9255 (2001): 539–545.
|
| [21] |
T. A. Doering, A. Crawford, J. M. Angelosanto, M. A. Paley, C. G. Ziegler, and E. J. Wherry, “Network Analysis Reveals Centrally Connected Genes and Pathways Involved in CD8+ T Cell Exhaustion versus Memory,” Immunity 37, no. 6 (2012): 1130–1144.
|
| [22] |
J. M. Chan, A. Quintanal-Villalonga, V. R. Gao, et al., “Signatures of Plasticity, Metastasis, and Immunosuppression in an Atlas of human Small Cell Lung Cancer,” Cancer Cell 39, no. 11 (2021): 1479–1496 e18.
|
| [23] |
C. M. Rudin, J. T. Poirier, L. A. Byers, et al., “Molecular Subtypes of Small Cell Lung Cancer: A Synthesis of human and Mouse Model Data,” Nature Reviews Cancer 19, no. 5 (2019): 289–297.
|
| [24] |
M. D. Borromeo, T. K. Savage, R. K. Kollipara, et al., “ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs,” Cell Reports 16, no. 5 (2016): 1259–1272.
|
| [25] |
C. Y. McLean, D. Bristor, M. Hiller, et al., “GREAT Improves Functional Interpretation of Cis-regulatory Regions,” Nature Biotechnology 28, no. 5 (2010): 495–501.
|
| [26] |
A. Hutloff, A. M. Dittrich, K. C. Beier, et al., “ICOS Is an Inducible T-cell co-stimulator Structurally and Functionally Related to CD28,” Nature 397, no. 6716 (1999): 263–266.
|
| [27] |
V. Ling, P. W. Wu, H. F. Finnerty, et al., “Cutting Edge: Identification of GL50, a Novel B7-Like Protein That Functionally Binds to ICOS Receptor,” Journal of Immunology 164, no. 4 (2000): 1653–1657.
|
| [28] |
Y. Simoni, M. Fehlings, H. N. Kloverpris, et al., “Human Innate Lymphoid Cell Subsets Possess Tissue-Type Based Heterogeneity in Phenotype and Frequency,” Immunity 48, no. 5 (2018): 1060.
|
| [29] |
M. A. Kunicki, L. C. Amaya Hernandez, K. L. Davis, R. Bacchetta, and M. G. Roncarolo, “Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry,” Journal of Immunology 200, no. 1 (2018): 336–346.
|
| [30] |
V. R. Fonseca, F. Ribeiro, and L. Graca, “T Follicular Regulatory (Tfr) Cells: Dissecting the Complexity of Tfr-cell Compartments,” Immunological Reviews 288, no. 1 (2019): 112–127.
|
| [31] |
J. S. Lim, A. Ibaseta, M. M. Fischer, et al., “Intratumoural Heterogeneity Generated by Notch Signalling Promotes Small-cell Lung Cancer,” Nature 545, no. 7654 (2017): 360–364, https://doi.org/10.1038/nature22323.
|
| [32] |
S. Jin, C. F. Guerrero-Juarez, L. Zhang, et al., “Inference and Analysis of Cell-cell Communication Using CellChat,” Nature Communications 12, no. 1 (2021): 1088.
|
| [33] |
L. Valdez Capuccino, T. Kleitke, B. Szokol, et al., “CDK9 inhibition as an Effective Therapy for Small Cell Lung Cancer,” Cell Death & Disease 15, no. 5 (2024): 345.
|
| [34] |
K. P. Burke, A. Chaudhri, G. J. Freeman, and A. H. Sharpe, “The B7:CD28 family and Friends: Unraveling Coinhibitory Interactions,” Immunity 57, no. 2 (2024): 223–244.
|
| [35] |
H. Yu, T. A. Boyle, C. Zhou, D. L. Rimm, and F. R. Hirsch, “PD-L1 Expression in Lung Cancer,” Journal of Thoracic Oncology 11, no. 7 (2016): 964–975.
|
| [36] |
Y. Chu, E. Dai, Y. Li, et al., “Pan-cancer T Cell Atlas Links a Cellular Stress Response state to Immunotherapy Resistance,” Nature Medicine 29, no. 6 (2023): 1550–1562.
|
| [37] |
K. Chamoto, T. Yaguchi, M. Tajima, and T. Honjo, “Insights From a 30-year Journey: Function, Regulation and Therapeutic Modulation of PD1,” Nature Reviews Immunology 23, no. 10 (2023): 682–695.
|
| [38] |
K. E. de Visser and J. A. Joyce, “The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth,” Cancer Cell 41, no. 3 (2023): 374–403.
|
| [39] |
S. Yao, Y. Zhu, G. Zhu, et al., “B7-h2 is a Costimulatory Ligand for CD28 in human,” Immunity 34, no. 5 (2011): 729–740.
|
| [40] |
F. Amatore, L. Gorvel, and D. Olive, “Role of Inducible Co-Stimulator (ICOS) in Cancer Immunotherapy,” Expert Opinion on Biological Therapy 20, no. 2 (2020): 141–150.
|
| [41] |
Y. Yan, D. Sun, J. Hu, et al., “Multi-omic Profiling Highlights Factors Associated With Resistance to Immuno-chemotherapy in Non-small-cell Lung Cancer,” Nature Genetics 57, no. 1 (2025): 126–139.
|
| [42] |
C. M. Gay, C. A. Stewart, E. M. Park, et al., “Patterns of Transcription Factor Programs and Immune Pathway Activation Define Four Major Subtypes of SCLC With Distinct Therapeutic Vulnerabilities,” Cancer Cell 39, no. 3 (2021): 346-360 e7.
|
| [43] |
D. Aran, Z. Hu, and A. J. Butte, “xCell: Digitally Portraying the Tissue Cellular Heterogeneity Landscape,” Genome Biology 18, no. 1 (2017): 220.
|
| [44] |
B. Li, E. Severson, J. C. Pignon, et al., “Comprehensive Analyses of Tumor Immunity: Implications for Cancer Immunotherapy,” Genome Biology 17, no. 1 (2016): 174.
|
| [45] |
T. Li, J. Fan, B. Wang, et al., “TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells,” Cancer Research 77, no. 21 (2017): e108–e110.
|
| [46] |
I. Korsunsky, N. Millard, J. Fan, et al., “Fast, Sensitive and Accurate Integration of Single-cell Data With Harmony,” Nature Methods 16, no. 12 (2019): 1289–1296.
|
| [47] |
X. Zhu, L. Sun, N. Song, et al., “Safety and Effectiveness of Neoadjuvant PD-1 Inhibitor (toripalimab) plus Chemotherapy in Stage II-III NSCLC (LungMate 002): An Open-label, Single-arm, Phase 2 Trial,” BMC Medicine [Electronic Resource] 20, no. 1 (2022): 493.
|
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