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Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as complementary biomarker for immune checkpoint inhibition in non-small-cell lung cancer
Open accessAbstract
PURPOSE Biomarkers on the basis of tumor-infiltrating lymphocytes (TIL) are potentially valuable in predicting the effectiveness of immune checkpoint inhibitors (ICI). However, clinical application remains challenging because of methodologic limitations and laborious process involved in spatial analysis of TIL distribution in whole-slide images (WSI). METHODS We have developed an artificial intelligence (AI)–powered WSI analyzer of TIL in the tumor microenvironment that can define three immune phenotypes (IPs): inflamed, immune-excluded, and immune-desert. These IPs were correlated with tumor response to ICI and survival in two independent cohorts of patients with advanced non–small-cell lung cancer (NSCLC). RESULTS Inflamed IP correlated with enrichment in local immune cytolytic activity, higher response rate, and prolonged progression-free survival compared with patients with immune-excluded or immune-desert phenotypes. At the WSI level, there was significant positive correlation between tumor proportion score (TPS) as determined by the AI model and control TPS analyzed by pathologists ( P < .001). Overall, 44.0% of tumors were inflamed, 37.1% were immune-excluded, and 18.9% were immune-desert. Incidence of inflamed IP in patients with programmed death ligand-1 TPS at < 1%, 1%-49%, and ≥ 50% was 31.7%, 42.5%, and 56.8%, respectively. Median progression-free survival and overall survival were, respectively, 4.1 months and 24.8 months with inflamed IP, 2.2 months and 14.0 months with immune-excluded IP, and 2.4 months and 10.6 months with immune-desert IP. CONCLUSION The AI-powered spatial analysis of TIL correlated with tumor response and progression-free survival of ICI in advanced NSCLC. This is potentially a supplementary biomarker to TPS as determined by a pathologist.
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“Numerous studies have demonstrated the potential for using AI to predict immunotherapy biomarkers from H&E images of patients with NSCLC, including tumor mutation burden (TMB; ref. 76), PD-L1 expression (105), and TILs (106, 107).”
From Artificial Intelligence in Oncology: Current Landscape, Challenges, and Future Directions (2024) · cites this paper as [106]
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“5%).(24,25) Distribution of IP by baseline clinical attributes and smoking history was investigated, and there was no correlation between IP and smoking status, liver metastasis, and lung immune prognostic index score(26); however, some correlation existed between IP and pleural effusion andbrainmetastasis at the poin…”
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- US Food and Drug Administration, 2020, PD-L1 IHC 22C3 pharmDx—P150013/S014
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“Similarly, AI-mediated analysis of tumor-infiltrating lymphocytes in advanced non–small-cell lung cancer (NSCLC) identified three immune phenotypes that correlated with response to immune checkpoint inhibitors and progression-free survival, which is challenging by manual quantification [98].”
BackgroundYu, J., Kong, X., & Feng, Y. (2025) · Cancer Drug Resistance · doi:10.20517/cdr.2025.14 · Cited by 32
Immunophenotyping of pulmonary sarcomatoid carcinoma
Ma, Y., Li, W., Li, Z., Chen, J., Wang, H., Jiang, T., & Zhu, J. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.976739 · Cited by 29
Park, C., Jeong, D. Y., Choi, Y., Oh, Y. J., Kim, J., Ryu, J., Paeng, K., Lee, S., Ock, C., & Lee, H. Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1038089 · Cited by 30
“Sun et al. (11) published the results of a radiomic signature model that predicts CD8 cells based on CD8B geneassociated signatures in NSCLC tumors and correlated this with ICI treatment outcomes.”
BackgroundMethodInfluentialImplications of different cell death patterns for prognosis and immunity in lung adenocarcinoma
Zhou, Y., Gao, W., Xu, Y., Wang, J., Wang, X., Shan, L., Lijuan, D., Sun, Q., Li, H., & Liu, F. (2023) · npj Precision Oncology · doi:10.1038/s41698-023-00456-y · Cited by 28
Bang, Y. H., Lee, C., Bang, K., Kim, H., Kim, K., Jeong, J. H., Park, I., Ryoo, B., Lee, D. K., Choi, H. J., et al. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-24-1265 · Cited by 28
Yu, A., Hu, J., Fu, L., Huang, G., Deng, D., Zhang, M., Wang, Y., Shu, G., Jing, L., Li, H., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007230 · Cited by 30
Rugambwa, T. K., Abdihamid, O., Zhang, X., Peng, Y., Cai, C., Shen, H., Zeng, S., & Qiu, W. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1181248 · Cited by 27
Lin, H., Hua, J., Gong, Z., Chen, M., Qiu, B., Wu, Y., He, W., Wang, Y., Feng, Z., Liang, Y., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217557 · Cited by 30
Schuiveling, M., Liu, H., Eek, D., Breimer, G. E., Suijkerbuijk, K. P. M., Blokx, W. A. M., & Veta, M. (2025) · GigaScience · doi:10.1093/gigascience/giaf011 · Cited by 26
Dasgupta, S. (2024) · OMICS A Journal of Integrative Biology · doi:10.1089/omi.2024.0175 · Cited by 25
Kim, H., Shin, J., Hyung, J., Lee, H., Moon, M., Ma, J., Park, Y. S., & Ryu, M. (2024) · Gastric Cancer · doi:10.1007/s10120-024-01566-7 · Cited by 25
Wu, M., Zhu, C., Yang, J., Cheng, S., Yang, X., Gu, S., Xu, S., Wu, Y., Shen, W., Huang, S., et al. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1069673 · Cited by 24
Zhang, H., Chen, L., Li, L., Liu, Y., Das, B., Zhai, S., Tan, J., Jiang, Y., Turco, S., Yao, Y., et al. (2025) · npj Precision Oncology · doi:10.1038/s41698-025-00866-0 · Cited by 25
Shibaki, R., Fujimoto, D., Nozawa, T., Sano, A., Kitamura, Y., Fukuoka, J., Sato, Y., Kijima, T., Matsumoto, H., Yokoyama, T., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-007987 · Cited by 22
“15 16 Therefore, to develop an objective biomarker for assessing the efficacy of immunotherapy using the TIME, the precise and objective spatial analysis of the complex positioning of inflammatory and tumor cells should be performed using machine learning.”
MethodAiZynth impact on medicinal chemistry practice at AstraZeneca
Shields, J. D., Howells, R., Lamont, G. M., Leilei, Y., Madin, A., Reimann, C. E., Rezaei, H., Reuillon, T. D., Smith, B., Thomson, C., et al. (2024) · RSC Medicinal Chemistry · doi:10.1039/d3md00651d · Cited by 22
Kim, H., Kim, S., Choi, S., Park, C., Park, S., Pereira, S., Ma, M., Yoo, D., Paeng, K., Jung, W., et al. (2024) · JCO Precision Oncology · doi:10.1200/po.23.00556 · Cited by 22
Han, D., Li, H., Zheng, X., Fu, S., Wei, R., Zhao, Q., Liu, C., Wang, Z., Huang, W. C., & Hao, S. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1453232 · Cited by 21
Lin, H., Hua, J., Wang, Y., Chen, M., Liang, Y., Yan, L., Zhao, W., Luo, S., Hong, D., Chen, X., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010723 · Cited by 25
Saberzadeh-Ardestani, B., Graham, R. P., McMahon, S., Ahanonu, E., Shi, Q., Williams, C., Hubbard, A., Zhang, W., Murányi, A., Yan, D., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-1109 · Cited by 20
Gill, G. S., Kharb, S., Goyal, G., Das, P., Kurdia, K. C., Dhar, R., & Karmakar, S. (2025) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2025.2504906 · Cited by 19
Artificial intelligence for radiopharmaceutical and molecular imaging
Tao, J., Liang, L., Hao, S., Chen, Y., Yang, Z., Cai, Y., & Zhu, H. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.09.039 · Cited by 23
“Based on pathomics, Park et al. 138 developed Lunit SCOPE IO, a spatial analysis model for tumor-infiltrating lymphocytes (TIL).”
Zeng, W., Wang, J., Yang, J., Chen, Z., Cui, Y., Li, Q., Luo, G., Ding, H., Ju, S., Li, B., et al. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1217590 · Cited by 18
Artificial intelligence in clinical trials of lung cancer: Current and future prospects
Zhang, Y., You, P., Liu, R., Lu, Y., Li, J., Lei, Y., Wu, S., & Zhou, H. (2024) · Intelligent Oncology · doi:10.1016/j.intonc.2024.11.003 · Cited by 18
Heo, J., Lee, H., Seog, Y., Kim, S., Baek, J., Park, H., Seo, K., Kim, G. S., Cho, H., Baik, M., et al. (2023) · Stroke · doi:10.1161/strokeaha.123.043127 · Cited by 17
Artificial Intelligence–Powered Spatial Analysis of Immune Phenotypes in Resected Pancreatic Cancer
Kim, H. M., Choi, J. H., Lim, Y., Yoon, S. J., Jang, K., Ock, C., Choi, Y. H., Joe, C., Song, S., Moon, J., et al. (2025) · JAMA Surgery · doi:10.1001/jamasurg.2025.1999 · Cited by 17
Hegi‐Johnson, F., Rudd, S. E., Wichmann, C. W., Akhurst, T. J., Roselt, P. D., Sursock, S., Trinh, J., John, T., Devereux, L., Donnelly, P. S., et al. (2023) · International Journal of Radiation Oncology*Biology*Physics · doi:10.1016/j.ijrobp.2023.05.019 · Cited by 16
A Thorough Review of the Clinical Applications of Artificial Intelligence in Lung Cancer
Kotoulas, S., Spyratos, D., Porpodis, Κ., Domvri, K., Boutou, A., Kaimakamis, E., Mouratidou, C., Alevroudis, I., Dourliou, V., Tsakiri, K., et al. (2025) · Cancers · doi:10.3390/cancers17050882 · Cited by 16
Zeng, Y., Cai, Y., Chai, P., Mao, Y., Chen, Y., Wang, L., Zeng, K., Zhan, Z., Xie, Y., Li, C., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.961933 · Cited by 16
Characterisation of tumour-immune phenotypes and PD-L1 positivity in squamous bladder cancer
Jung, M., Rose, M., Knuechel, R., Loeffler, C. M. L., Muti, H. S., Kather, J. N., Gaisa, N. T., & on behalf of the German Study Group of Bladder Cancer (DFBK e.V.) (2023) · BMC Cancer · doi:10.1186/s12885-023-10576-0 · Cited by 16
Parra, E. R., Ilié, M., Wistuba, I. I., & Hofman, P. M. (2023) · British Journal of Cancer · doi:10.1038/s41416-023-02318-7 · Cited by 15
Kerepesi, C., Abushukair, H. M., Ricciuti, B., Nassar, A. H., Adib, E., Alessi, J. V., Pecci, F., Rakaee, M., Fadlullah, M. Z. H., Tőkés, A.-M., et al. (2024) · JCO Precision Oncology · doi:10.1200/po.23.00439 · Cited by 15
Hamada, K., Murakami, R., Ueda, A., Kashima, Y., Miyagawa, C., Taki, M., Yamanoi, K., Yamaguchi, K. D., Hamanishi, J., Minamiguchi, S., et al. (2024) · American Journal Of Pathology · doi:10.1016/j.ajpath.2024.02.016 · Cited by 16
Yang, J., Zheng, J., Qiu, J., Zhang, M., Liu, L., Wang, Z., Zheng, Q., Liu, Y., Chen, M., & Li, J. (2023) · Journal of Immunology Research · doi:10.1155/2023/4275998 · Cited by 14
“better OS than TIL-negative cases when compared with melanoma, breast, lung, liver, and colorectal cancers [6, 7].”
BackgroundHeterogeneity of the tumor immune microenvironment and clinical interventions
Jin, Z., Zhou, Q., Cheng, J., Jia, Q., & Zhu, B. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-1015-9 · Cited by 14
Solving the puzzle of what makes immunotherapies work
Ma, X., & Chan, T. A.-T. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.06.011 · Cited by 15
Bang, Y. H., Park, G., Oh, J. W., Hwang, S., Jeong, J.-G., Lee, B., Joe, C. Y., Kim, H. M., Kim, J., Park, S., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-012374 · Cited by 13
“46 Conversely, patients with L858R mutations had preserved TIL levels and demonstrated increased EC abundance, possibly because of the differential modulation of vascular remodeling or immune signaling pathways post-TKI.”
InfluentialRojas, F. R., Parra, E. R., Wistuba, I. I., Haymaker, C., & Soto, L. M. S. (2022) · Cancers · doi:10.3390/cancers14112775 · Cited by 14
Qu, H., Jiang, J., Zhan, X., Liang, Y., Guo, Q., Liu, P., Lü, L., Yang, Y., Xu, W., Zhang, Y., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-54222-6 · Cited by 13
Automated tumor immunophenotyping predicts clinical benefit from anti‐PD‐L1 immunotherapy
Xiao, L., Eastham, J., Giltnane, J. M., Zou, W., Zijlstra, A., Tabatsky, E., Banchereau, R., Chang, C., Nabet, B. Y., Patil, N. S., et al. (2024) · The Journal of Pathology · doi:10.1002/path.6274 · Cited by 13
A real‐world study of immune checkpoint inhibitors in advanced triple‐negative breast cancer
Zhang, Z., Zhang, Y., Liu, C., Shao, J., Chen, Y., Zhu, Y., Zhang, L., Qin, B., Kong, Z., Wang, X., et al. (2023) · Cancer Innovation · doi:10.1002/cai2.70 · Cited by 12
“Previous studies have found that the PD ‐ L1 expression levels, percentage of CD8 + T cells, TIL density, and tumor mutational burden (TMB) may be related to the efficacy of immunotherapy [12 – 14].”
BackgroundAlshorman, J., Mehran, M. J., Bahrami, Y., Mohammadzadeh, S., Barzigar, R., Morshedi, M., Haider, K. H., Tembo, K. M., Rong, S.-J., Jadgal, N., et al. (2026) · Clinical and Experimental Medicine · doi:10.1007/s10238-026-02107-5 · Cited by 15
Pembrolizumab for Patients with Relapsed or Refractory Extranodal NK/T-Cell Lymphoma in Korea
Lee, J. Y., Kwon, J. H., Hur, J. Y., Yi, J. H., Lee, J., Cho, H., Do, Y. R., Jo, J., Kang, H. J., Koh, Y., et al. (2023) · Cancer Research and Treatment · doi:10.4143/crt.2023.1042 · Cited by 12
“AI-powered spatial analysis of IP was found to correlate with tumor response and PFS with ICIs in advanced non–small cell lung cancer, demonstrating the therapeutic applicability of IP as a biomarker of ICIs [30].”
Background
Metadata
- Authors
- Park, S., Ock, C.-Y., Kim, H., Pereira, S., Park, S., Ma, M., Choi, S., Kim, S., Shin, S., Aum, B. J., Paeng, K., Yoo, D., Cha, H., Park, S., Suh, K. J., Jung, H. A., Kim, S. H., Kim, Y. J., Sun, J.-M., Chung, J.-H., Ahn, J. S., Ahn, M.-J., Lee, J. S., Park, K., Song, S. Y., Bang, Y.-J., Choi, Y.-L., Mok, T. S., & Lee, S.-H.
- Affiliations
- Samsung Medical Center (KR)
- Lunit (South Korea) (KR)
- Seoul National University Bundang Hospital (KR)
- Lunit, Seoul, Republic of Korea
- Ajou University (KR)
- Seoul National University (KR)
- Chinese University of Hong Kong (HK)
- Corresponding author
- Lee, Se-Hoon
- ORCID
- Park, Sehhoon
- Ock, Chan-Young
- Kim, Hyojin
- Park, Seonwook
- Ma, Minuk
- Choi, Sangjoon
- Kim, Seokhwi
- Shin, Seunghwan
- Aum, Brian Jaehong
- Cha, Hongui
- Park, Sunyoung
- Suh, Koung Jin
- Jung, Hyun Ae
- Kim, Se Hyun
- Kim, Yu Jung
- Sun, Jong-Mu
- Chung, Jin-Haeng
- Ahn, Jin Seok
- Ahn, Myung-Ju
- Lee, Jong Seok
- Park, Keunchil
- Bang, Yung-Jue
- Choi, Yoon-La
- Mok, Tony S.
- Lee, Se-Hoon
- Venue
- Journal of Clinical Oncology
- Published
- 2022-06-10
- Volume
- 40
- Issue
- 17
- Pages
- 1916-1928
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC9177249
- OpenAlex
- W4220803499
- Cited by
- 280
- References
- 29
- Citations by year
- 2026: 46 · 2025: 76 · 2024: 75 · 2023: 56 · 2022: 27
- FWCI
- 24.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- AJOU Open Repository (Ajou University) (submittedVersion, cc-by-nc-nd)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- Lunit
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Physical Sciences › Computer Science › Artificial Intelligence › AI in cancer detection
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiomics and Machine Learning in Medical Imaging
- Keywords
- tumor-infiltrating lymphocytes, immune checkpoint inhibitors, non-small cell lung cancer, tumor microenvironment, immunophenotype, immune-excluded tumors, tumor proportion score, PD-L1 expression, whole slide image analysis, artificial intelligence, predictive biomarkers, progression-free survival, overall survival
- MeSH terms
- Immune Checkpoint Inhibitors, Artificial Intelligence, Carcinoma, Non-Small-Cell Lung, Humans, Lung Neoplasms, Biomarkers, Lymphocytes, Tumor-Infiltrating, Tumor Microenvironment, B7-H1 Antigen, Spatial Analysis
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