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
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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.

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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.

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