https://doi.org/10.4081/monaldi.2025.3288
Programmed cell death-ligand 1 expression and CD8 positive tumor-infiltrating lymphocyte density in non-small cell lung carcinoma and its association with histopathological grading
Submitted: December 2, 2024
Accepted: December 6, 2024
Published: February 21, 2025
Accepted: December 6, 2024
Abstract Views: 12
PDF_EARLY VIEW: 5
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Non-small cell lung carcinoma (NSCLC), comprising 85% of lung cancers, remains a leading cause of cancer mortality despite advances in treatment. Immunotherapy, particularly immune checkpoint inhibitors targeting the PD-1/PD-L1 axis, has revolutionized therapy, though outcomes vary. This study aimed to explore the association between PD-L1 expression, CD8 tumor-infiltrating lymphocyte (TIL) density, and histopathological grading in NSCLC. Our retrospective, single-centered cohort comprised 64 biopsy samples of NSCLC. PD-L1 and CD8 TILs density was assessed through immunohistochemistry. We also classified the tumors into four groups based on the PD-L1 and CD8-positive TIL statuses and evaluated their association with clinicopathological parameters. Male subjects were the predominant population in the study group (86%), with a mean age of 60 years. Most of the cases were smokers/ex-smokers (70.3%). Among 64 cases, PD-L1 positivity was observed in 62.5%, correlating with poorly differentiated tumors (grade 3) (p=0.03), suggesting its association with poor prognosis. Among PD-L1 positive cases, 55% had high expression and 45% had low expression. CD8 TIL density was low in 62.5% of cases and showed no significant correlation with clinical variables. Combined analysis revealed that 42.19% of cases were PD-L1+/CD8 low, a phenotype indicative of immune evasion and aggressive tumor behavior. Overall, our results emphasize that while PD-L1 immunohistochemistry remains a critical tool for identifying candidates for immunotherapy, it is not a standalone predictor of treatment response. Integrating CD8 TIL density provides additional prognostic information, potentially guiding more personalized treatment strategies.
Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229-63.
DOI: https://doi.org/10.3322/caac.21834
Singh N, Agrawal S, Jiwnani S, et al. Lung Cancer in India. J Thorac Oncol 2021;16:1250-66.
DOI: https://doi.org/10.1016/j.jtho.2021.02.004
Nath A, Sathishkumar K, Das P, et al. A clinicoepidemiological profile of lung cancers in India - Results from the National Cancer Registry Programme. Indian J Med Res 2022;155:264-72.
DOI: https://doi.org/10.4103/ijmr.ijmr_1364_21
Molina JR, Yang P, Cassivi SD, et al. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc 2008;83:584-94.
DOI: https://doi.org/10.4065/83.5.584
Schabath MB, Cote ML. Cancer progress and priorities: lung cancer. Cancer Epidemiol Biomarkers Prev 2019;28:1563-79.
DOI: https://doi.org/10.1158/1055-9965.EPI-19-0221
Murali AN, Radhakrishnan V, Ganesan TS, et al. Outcomes in lung cancer: 9-year experience from a tertiary cancer center in India. J Glob Oncol 2017;3:459-68.
DOI: https://doi.org/10.1200/JGO.2016.006676
Soo RA, Stone ECA, Cummings KM, et al. Scientific advances in thoracic oncology 2016. J Thorac Oncol 2017;12:1183-209.
DOI: https://doi.org/10.1016/j.jtho.2017.05.019
Ferrara R, Mezquita L, Besse B. Progress in the management of advanced thoracic malignancies in 2017. J Thorac Oncol 2018;13:301-22.
DOI: https://doi.org/10.1016/j.jtho.2018.01.002
Anagnostou VK, Brahmer JR. Cancer immunotherapy: a future paradigm shift in the treatment of non-small cell lung cancer. Clin Cancer Res 2015;21:976-84.
DOI: https://doi.org/10.1158/1078-0432.CCR-14-1187
Doroshow DB, Sanmamed MF, Hastings K, et al. Immunotherapy in non-small cell lung cancer: facts and hopes. Clin Cancer Res 2019;25:4592-602.
DOI: https://doi.org/10.1158/1078-0432.CCR-18-1538
Shea M, Costa DB, Rangachari D. Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches. Ther Adv Respir Dis 2016;10:113-29.
DOI: https://doi.org/10.1177/1753465815617871
World Health Organization. WHO classification of tumours editorial board. Thoracic tumours. 2021. Available from: https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/Thoracic-Tumours-2021.
Parra ER, Villalobos P, Mino B, Rodriguez-Canales J. Comparison of different antibody clones for immunohistochemistry detection of programmed cell death ligand 1 (PD-L1) on non-small cell lung carcinoma. Appl Immunohistochem Mol Morphol 2018;26:83-93.
DOI: https://doi.org/10.1097/PAI.0000000000000531
Shimoji M, Shimizu S, Sato K, et al. Clinical and pathologic features of lung cancer expressing programmed cell death ligand 1 (PD-L1). Lung Cancer 2016;98:69-75.
DOI: https://doi.org/10.1016/j.lungcan.2016.04.021
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.
DOI: https://doi.org/10.1038/nrc3239
Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 2020;10:727-42.
Doroshow DB, Bhalla S, Beasley MB, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 2021;18:345-62.
DOI: https://doi.org/10.1038/s41571-021-00473-5
Liu T, Ding S, Dang J, et al. First-line immune checkpoint inhibitors for advanced non-small cell lung cancer with wild-type epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK): a systematic review and network meta-analysis. J Thorac Dis 2019;11:2899-912.
DOI: https://doi.org/10.21037/jtd.2019.07.45
Akinboro O, Larkins E, Pai-Scherf LH, et al. FDA approval summary: pembrolizumab, atezolizumab, and cemiplimab-rwlc as single agents for first-line treatment of advanced/metastatic PD-L1-high NSCLC. Clin Cancer Res 2022;28:2221-8.
DOI: https://doi.org/10.1158/1078-0432.CCR-21-3844
Negrao MV, Lam VK, Reuben A, et al. 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;14:1021-31.
DOI: https://doi.org/10.1016/j.jtho.2019.02.008
Cao X. Regulatory T cells and immune tolerance to tumors. Immunol Res 2010;46:79-93.
DOI: https://doi.org/10.1007/s12026-009-8124-7
Rathore AS, Kumar S, Konwar R, et al. Presence of CD3+ tumor infiltrating lymphocytes is significantly associated with good prognosis in infiltrating ductal carcinoma of breast. Indian J Cancer 2013;50:239-44.
DOI: https://doi.org/10.4103/0019-509X.118744
Chen Y, Yu D, Qian H, et al. CD8+ T cell-based cancer immunotherapy. J Transl Med 2024;22:394.
DOI: https://doi.org/10.1186/s12967-024-05134-6
Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer Res 2015;75:2139-45.
DOI: https://doi.org/10.1158/0008-5472.CAN-15-0255
Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823-33.
DOI: https://doi.org/10.1056/NEJMoa1606774
Rakaee M, Kilvaer TK, Dalen SM, et al. Evaluation of tumor-infiltrating lymphocytes using routine H&E slides predicts patient survival in resected non-small cell lung cancer. Hum Pathol 2018;79:188-98.
DOI: https://doi.org/10.1016/j.humpath.2018.05.017
Elsaka RO, Helal SM, Abdelhady AM, et al. Immunohistochemical expression of CD8, CTLA4, and PD-L1 in NSCLC of smokers versus non-smokers and its effect on prognosis. Alexandria J Med 2022;58:92-101.
DOI: https://doi.org/10.1080/20905068.2022.2101083
El-Guindy DM, Helal DS, Sabry NM, Abo El-Nasr M. Programmed cell death ligand-1 (PD-L1) expression combined with CD8 tumor infiltrating lymphocytes density in non-small cell lung cancer patients. J Egypt Natl Canc Inst 2018;30:125-31.
DOI: https://doi.org/10.1016/j.jnci.2018.08.003
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.
DOI: https://doi.org/10.3322/caac.21492
Jin Y, Shen X, Pan Y, et al. Correlation between PD-L1 expression and clinicopathological characteristics of non-small cell lung cancer: a real-world study of a large Chinese cohort. J Thorac Dis 2019;11:4591-601.
DOI: https://doi.org/10.21037/jtd.2019.10.80
Pawelczyk K, Piotrowska A, Ciesielska U, et al. Role of PD-L1 expression in non-small cell lung cancer and their prognostic significance according to clinicopathological factors and diagnostic markers. Int J Mol Sci 2019;20:824.
DOI: https://doi.org/10.3390/ijms20040824
Rashed HE, Abdelrahman AE, Abdelgawad M, et al. Prognostic significance of programmed cell death ligand 1 (PD-L1), CD8+ tumor-infiltrating lymphocytes and p53 in non-small cell lung cancer: an immunohistochemical study. Turk Patoloji Derg 2017;1:211-22.
DOI: https://doi.org/10.5146/tjpath.2017.01398
Hirahara K, Ghoreschi K, Yang XP, et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 2012;36:1017-30.
DOI: https://doi.org/10.1016/j.immuni.2012.03.024
Sundar R, Soong R, Cho BC, et al. Immunotherapy in the treatment of non-small cell lung cancer. Lung Cancer 2014;85:101-9.
DOI: https://doi.org/10.1016/j.lungcan.2014.05.005
Mu CY, Huang JA, Chen Y, et al. High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 2011;28:682-8.
DOI: https://doi.org/10.1007/s12032-010-9515-2
Cooper WA, Tran T, Vilain RE, et al. PD-L1 expression is a favourable prognostic factor in early-stage non-small cell carcinoma. Lung Cancer 2015;89:181-8.
DOI: https://doi.org/10.1016/j.lungcan.2015.05.007
Tang Y, Fang W, Zhang Y, et al. The association between PD-L1 and EGFR status and the prognostic value of PD-L1 in advanced non-small cell lung cancer patients treated with EGFR-TKIs. Oncotarget 2015;6:14209-19.
DOI: https://doi.org/10.18632/oncotarget.3694
Igarashi T, Teramoto K, Ishida M, et al. Scoring of PD-L1 expression intensity on pulmonary adenocarcinomas and the correlations with clinicopathological factors. ESMO Open 2016;1:e000083.
DOI: https://doi.org/10.1136/esmoopen-2016-000083
Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression in non-small cell lung cancer. Lab Invest 2014;94:107-16.
DOI: https://doi.org/10.1038/labinvest.2013.130
Blichárová A, Tancoš V, Benetinová Z, et al. Programmed death ligand-1 expression and its association with the degree of differentiation and the presence of necrosis in non-small cell lung carcinoma. Pathol Res Pract 2023;242:154296.
DOI: https://doi.org/10.1016/j.prp.2022.154296
Jiang L, Su X, Zhang T, et al. PD-L1 expression and its relationship with oncogenic drivers in non-small cell lung cancer (NSCLC). Oncotarget 2017;8:26845-57.
DOI: https://doi.org/10.18632/oncotarget.15839
Angell HK, Bruni D, Barrett JC, et al. The immunoscore: colon cancer and beyond. Clin Cancer Res 2020;26:332-9.
DOI: https://doi.org/10.1158/1078-0432.CCR-18-1851
Schalper KA, Brown J, Carvajal-Hausdorf D, et al. Objective measurement and clinical significance of TILs in non–small cell lung cancer. J Natl Cancer Inst 2015;107:dju435.
DOI: https://doi.org/10.1093/jnci/dju435
Zhuang X, Xia X, Wang C, et al. A high number of CD8+ T cells infiltrated in NSCLC tissues is associated with a favorable prognosis. Appl Immunohistochem Mol Morphol 2010;18:24-8.
DOI: https://doi.org/10.1097/PAI.0b013e3181b6a741
Donnem T, Hald SM, Paulsen EE, et al. Stromal CD8+ T-cell density—a promising supplement to TNM staging in non–small cell lung cancer. Clin Cancer Res 2015;21:2635-43.
DOI: https://doi.org/10.1158/1078-0432.CCR-14-1905
Wakabayashi O, Yamazaki K, Oizumi S, et al. CD4+ T cells in cancer stroma, not CD8+ T cells in cancer cell nests, are associated with favorable prognosis in human non-small cell lung cancers. Cancer Sci 2003;94:1003-9.
DOI: https://doi.org/10.1111/j.1349-7006.2003.tb01392.x
Mori M, Ohtani H, Naito Y, et al. Infiltration of CD8+ T cells in non-small cell lung cancer is associated with dedifferentiation of cancer cells, but not with prognosis. Tohoku J Exp Med 2000;191:113-8.
DOI: https://doi.org/10.1620/tjem.191.113
Nowicki TS, Akiyama R, Huang RR, et al. Infiltration of CD8 T cells and expression of PD-1 and PD-L1 in synovial sarcoma. Cancer Immunol Res 2017;5:118-26.
DOI: https://doi.org/10.1158/2326-6066.CIR-16-0148
Ameratunga M, Asadi K, Lin X, et al. PD-L1 and tumor infiltrating lymphocytes as prognostic markers in resected NSCLC. PLoS One 2016;11:e0153954.
DOI: https://doi.org/10.1371/journal.pone.0153954
Hwang S, Kwon AY, Jeong JY, et al. Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer. Sci Rep 2020;10:643.
DOI: https://doi.org/10.1038/s41598-019-57218-9
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 2014;515:563-7.
DOI: https://doi.org/10.1038/nature14011
Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 2014;20:5064-74.
DOI: https://doi.org/10.1158/1078-0432.CCR-13-3271
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014;515:568-71.
DOI: https://doi.org/10.1038/nature13954
McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 2016;351:1463-9.
DOI: https://doi.org/10.1126/science.aaf1490
Ribas A, Hu-Lieskovan S. What does PD-L1 positive or negative mean? J Exp Med 2016;213:2835-40.
DOI: https://doi.org/10.1084/jem.20161462
Ethics Approval
Ethical clearance taken from the Institutional Ethics Committee, VMMC, and Safdarjung Hospital, New Delhi, with serial no. IEC/VMMC/SJH/Thesis/2023-03/CC-241 dated 27th March 2023.How to Cite
Sureka, Niti, Sheetal Arora, Pranav Ish, and Geetika Khanna. 2025. “Programmed Cell Death-Ligand 1 Expression and CD8 Positive Tumor-Infiltrating Lymphocyte Density in Non-Small Cell Lung Carcinoma and Its Association With Histopathological Grading”. Monaldi Archives for Chest Disease, February. https://doi.org/10.4081/monaldi.2025.3288.
Copyright (c) 2025 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Matteo Gelardi, Mario Notargiacomo, Eleonora Maria Consiglia Trecca, Michele Cassano, Giorgio Ciprandi, COVID-19: the difference between the nose and the lung , Monaldi Archives for Chest Disease: Vol. 91 No. 2 (2021)
- Evgenia I. Kalamara, Evangelos T. Ballas, Georgia Pitsiou, Guergana Petrova, Pulmonary rehabilitation for cystic fibrosis: A narrative review of current literature , Monaldi Archives for Chest Disease: Vol. 91 No. 2 (2021)
- G. Ciprandi, G.L. Marseglia, M.A. Tosca, Allergen-specific immunotherapy: an update on immunological mechanisms of action , Monaldi Archives for Chest Disease: Vol. 65 No. 1 (2006): Pulmonary series
- Manju Bala, Akhlesh Rajpoot, Dinesh Chandra Punera, Suyash Singh Rathore, Hormonal harmony disrupted: hypothyroidism and diabetes mellitus in interstitial lung disease. An observational study , Monaldi Archives for Chest Disease: Early Access
- Josuel Ora, Angelo Coppola, Andrea Perduno, Gian Marco Manzetti, Ermanno Puxeddu, Paola Rogliani, Acute effect of oxygen therapy on exercise tolerance and dyspnea perception in ILD patients , Monaldi Archives for Chest Disease: Vol. 92 No. 2 (2022)
- Biagio Polla, Roflumilast is effective in reducing COPD related exacerbations and improving CAT score , Monaldi Archives for Chest Disease: Vol. 79 No. 3-4 (2013): Pulmonary series - Supplement 1
- A.E. Erbaycu, I. Karasu, F.G. Özdemirkıran, N. Yücel, A. Özsöz, O. Bilgir, Endobronchial low-grade MALT lymphoma causing unilateral hypertranslucency , Monaldi Archives for Chest Disease: Vol. 61 No. 4 (2004): Pulmonary series
- Alberto Fantin, Nadia Castaldo, Paolo Vailati, Giuseppe Morana, Vincenzo Patruno, Full medical treatment of COVID-19 associated large pneumothorax - A case report , Monaldi Archives for Chest Disease: Vol. 92 No. 1 (2022)
- Carmine Guarino, Ilaria Pedicelli, Francesco Perna, Valentina Di Spirito, Giuseppe Fiorentino, Fabio Procaccini, Gaetano Rea, E-cigarette, or vaping, product use Associated Lung Injury (EVALI): new scenarios for physicians and radiologists , Monaldi Archives for Chest Disease: Vol. 92 No. 3 (2022)
- F. Scafa, C.M. Minelli, R. Fonte, G.L. Rosso, M.I. Cappelli, S.M. Candura, Silicotuberculosis in the elderly: report of two cases , Monaldi Archives for Chest Disease: Vol. 61 No. 4 (2004): Pulmonary series
<< < 28 29 30 31 32 33 34 35 36 37 > >>
You may also start an advanced similarity search for this article.
