The dynamics of PD-L1 expression are poorly understood over the development of lung adenocarcinomas from pre-invasive lesions to fully invasive carcinomas. Given the importance of PD-L1 expression for the selection of patients to receive immunotherapy in the metastatic setting and possibly in the neoadjuvant setting, we sought to evaluate the agreement of PD-L1 expression in invasive and lepidic components of resected tumor specimens. We stained 86 adenocarcinomas for PD-L1 using the SP263 clone. We assessed the agreement of PD-L1 expression by tumor cells and immune cells between lepidic and invasive components. When both lepidic and invasive components were considered, PD-L1 positive immune cells and tumor cells were observed in 50 (58.1%) and 18 (20.9%) samples, respectively, using a ≥ 1% PD-L1 expression cutoff. Using a ≥ 1% cutoff for PD-L1 expression, positively stained tumor cells were observed in 11 (13%) lepidic and 15 (17%) invasive patterns, with agreement in 76 (88%) specimens and disagreement in 10 (12%) specimens (ĸ = 0.549). At ≥ 1% PD-L1 expression cutoff, PD-L1 positive immune cells were observed in 31 (35%) lepidic and 32 (37%) invasive patterns with an agreement of PD-L1 expression in 49 (57%) specimens and disagreement in 37 (43%) specimens (ĸ = 0.073). In our study of early stage adenocarcinomas of the lung, there was poor agreement in PD-L1 expression between paired invasive and lepidic components of tumors. Our data suggest that the non-invasive tumor components may not be as immunostimulatory as the invasive components, resulting in less adaptive expression of PD-L1.
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Langer CJ et al (2016) Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17(11):1497–1508
Paz-Ares L et al (2018) Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 379(21):2040–2051
Reck M et al (2016) Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 375(19):1823–1833
Antonia SJ et al (2018) Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 379(24):2342–2350
Kim MY et al (2015) Clinicopathological analysis of PD-L1 and PD-L2 expression in pulmonary squamous cell carcinoma: Comparison with tumor-infiltrating T cells and the status of oncogenic drivers. Lung Cancer 88(1):24–33
Kluger HM et al (2015) Characterization of PD-L1 expression and associated T-cell infiltrates in metastatic melanoma samples from variable anatomic sites. Clin Cancer Res 21(13):3052–3060
Madore J et al (2015) PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials. Pigment Cell Melanoma Res 28(3):245–253
Lee SM et al (2013) Invasive pulmonary adenocarcinomas versus preinvasive lesions appearing as ground-glass nodules: differentiation by using CT features. Radiology 268(1):265–273
Jones KD (2013) Whence lepidic?: the history of a Canadian neologism. Arch Pathol Lab Med 137(12):1822–1824
Travis WD et al (2015) The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 10(9):1243–1260
Araki K et al (2014) Excellent prognosis of lepidic-predominant lung adenocarcinoma: low incidence of lymphatic vessel invasion as a key factor. Anticancer Res 34(6):3153–3156
Xu L, Tavora F, Burke A (2013) Histologic features associated with metastatic potential in invasive adenocarcinomas of the lung. Am J Surg Pathol 37(7):1100–1108
Yanagawa N et al (2013) New IASLC/ATS/ERS classification and invasive tumor size are predictive of disease recurrence in stage I lung adenocarcinoma. J Thorac Oncol 8(5):612–618
Blomberg OS, Spagnuolo L, de Visser KE (2018) Immune regulation of metastasis: mechanistic insights and therapeutic opportunities. Dis Model Mech 11(10):dmm036236. https://doi.org/10.1242/dmm.036236
Mansfield AS et al (2016) Heterogeneity of programmed cell death ligand 1 expression in multifocal lung cancer. Clin Cancer Res 22(9):2177–2182
Hirsch FR et al (2017) PD-L1 Immunohistochemistry assays for lung cancer: results from phase 1 of the blueprint PD-L1 IHC assay comparison project. J Thorac Oncol 12(2):208–222
Hellmann MD et al (2017) Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Lancet Oncol 18(1):31–41
Krzywinski M et al (2009) Circos: an information aesthetic for comparative genomics. Genome Res 19(9):1639–1645
Ng Kee Kwong F et al (2018) Expression of PD-L1 correlates with pleomorphic morphology and histological patterns of non-small-cell lung carcinomas. Histopathology. 72(6):1024–1032
Terra S et al (2017) Temporal and spatial heterogeneity of programmed cell death 1-Ligand 1 expression in malignant mesothelioma. Oncoimmunology 6(11):e1356146
Terra S et al (2019) Heterogeneity of programmed death-ligand 1 expression in thymic epithelial tumours between initial specimen and synchronous or metachronous metastases or recurrences. Histopathology 74(2):364–367
Ilie M et al (2016) Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies. Ann Oncol 27(1):147–153
Mansfield AS et al (2016) Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol 27(10):1953–1958
Miyazawa T et al (2019) PD-L1 expression in non-small-cell lung cancer including various adenocarcinoma subtypes. Ann Thorac Cardiovasc Surg 25(1):1–9
Naso JR et al (2020) Intratumoral heterogeneity in programmed death-ligand 1 immunoreactivity is associated with variation in non-small cell lung carcinoma histotype. Histopathology 76(3):394–403
Jiang X et al (2019) Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 18(1):10
Mansfield AS et al (2018) Contraction of T cell richness in lung cancer brain metastases. Sci Rep 8(1):2171
Yu H et al (2016) PD-L1 expression in lung cancer. J Thorac Oncol 11(7):964–975
Adam J et al (2018) Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer. Ann Oncol 29(4):953–958
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Hazim, A., Majithia, N., Murphy, S.J. et al. Heterogeneity of PD-L1 expression between invasive and lepidic components of lung adenocarcinomas. Cancer Immunol Immunother (2021). https://doi.org/10.1007/s00262-021-02883-x