G Boulle1, Y Velut1, A Mansuet-Lupo2, L Gibault3, H Blons4, L Fournel5, A Boni1, I Cremer1, M Wislez6, V Duchatelle7, J Trédaniel8, S A Hammond9, R Herbst9, M Alifano10, P Giraud11, D Damotte12. 1. Institut National de La Santé et de La Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, inflammation and complement, Paris, France; University Paris Descartes, Paris, France; University Pierre et Marie Curie-Paris, Paris, France. 2. Institut National de La Santé et de La Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, inflammation and complement, Paris, France; University Paris Descartes, Paris, France; University Pierre et Marie Curie-Paris, Paris, France; Department of Pathology, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France. 3. Department of Pathology, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France. 4. University Paris Descartes, Paris, France; INSERM UMRS 1147, Paris, France; Department of Biochemistry, APHP, Hôpital Européen Georges Pompidou, Paris, France. 5. University Paris Descartes, Paris, France; Department of Thoracic Surgery, APHP, Hôpital Cochin, Paris, France; INSERM U1124, Paris, France. 6. Institut National de La Santé et de La Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, inflammation and complement, Paris, France; University Paris Descartes, Paris, France; Department of Respiratory Medicine, APHP, Hôpital Cochin, Paris, France. 7. Department of Pathology, St Joseph Hospital, Paris, France. 8. University Paris Descartes, Paris, France; INSERM U1124, Paris, France; Department of Oncology, St Joseph Hospital, Paris, France. 9. Research and Early Discovery, Oncology Research and Development, AstraZeneca, Gaithersburg, MD, USA. 10. Institut National de La Santé et de La Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, inflammation and complement, Paris, France; University Paris Descartes, Paris, France; University Pierre et Marie Curie-Paris, Paris, France; Department of Thoracic Surgery, APHP, Hôpital Cochin, Paris, France. 11. University Paris Descartes, Paris, France; APHP, Hôpital Européen Georges Pompidou, Department of Radiotherapy, Paris, France. 12. Institut National de La Santé et de La Recherche Médicale (INSERM), UMRS 1138, Cordeliers Research Center, Team Cancer, inflammation and complement, Paris, France; University Paris Descartes, Paris, France; University Pierre et Marie Curie-Paris, Paris, France; Department of Pathology, Assistance Publique - Hôpitaux de Paris (AP-HP), Hôpital Cochin, Paris, France. Electronic address: diane.damotte@aphp.fr.
Abstract
BACKGROUND: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. PATIENTS AND METHODS: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. RESULTS: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99-3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11-3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT. CONCLUSIONS: Intra-tumoural CD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy.
BACKGROUND: Radiotherapy is a standard of care for locally advanced stage III N2 non-small-cell lung carcinoma (NSCLC) combined with surgery/chemotherapy. Radiotherapy is hypothesised to induce tumour immunogenic cell death, to release neoantigen resulting in intra-tumoural immune infiltration and abscopal effect. Conversely, it has not been demonstrated if immune cells are necessary to drive radiotherapy efficacy and predict patient's survival. PATIENTS AND METHODS: We retrospectively analysed tumour samples and clinical data from 113 patients, 89 resected (PORT) and 24 non-resected (DRC) N2-NSCLC treated with chemotherapy and radiotherapy (same radiotherapy department from 2002 to 2015). The immune environment was characterised with in situ multiplex staining (CD8, FoxP3, PD-L1 and cytokeratin) and correlated with clinical data and survival. RESULTS: High density of CD8+ T cells was associated with OS (p = 0.04, HR = 1.93 [0.99-3.78]) and DFS (p = 0.003, HR = 2.42 [1.31-4.47]) in the PORT. High density of CD8+/FoxP3+ double positive cells was associated with OS (p = 0.01, HR = 1.97 [1.11-3.48]) in the whole population, with OS (p = 0.05, HR = 1.92 [0.98-3.74]) and PFS (p = 0.03, HR = 1.83 [1.03-3.23]) in the PORT without reaching significance for the DRC. Intermediate PD-L1 expression in tumour cells (TPS = 1-49%) was associated with a higher survival in the PORT. CONCLUSIONS:Intra-tumouralCD8+ T cell and particularly CD8+/FoxP3+ double positive T cell densities predict survival in stage III N2-NSCLC suggesting the need for a pre-existing intra-tumour immunity to mediate the action of radiotherapy. Density of CD8+/FoxP3+ cells was the best predictor of patient's survival in multivariate analysis and could represent a biomarker of radiotherapy efficacy.