Background The role of radiotherapy (RT) in immunotherapy-based (IO) combinatory approaches to advanced NSCLC is still uncertain due to its dual immune -suppressive and -stimulatory effect. We performed a longitudinal peripheral blood (PB) analysis to determine whether RT, by affecting immune cell phenotypes and dynamics, impacts on clinical outcome of IO-treated NSCLC patients. Methods PB samples were prospectively collected at baseline (T0) and first disease assessment (T1) on stage IV NSCLC undergoing 1st line IO-based regimens alone (RTnull) or combined with RT (RTpre, within 4 weeks before IO; RTpost, during IO). Flow cytometric analysis included CD3, CD8, CD4, NK, NKT, CD19, CD14 and Treg cells, expression of functional molecules (PD1, Granzyme B [GZB], Perforin [Perf]) and proliferative index (Ki67). PB parameters and their delta variation ([T1-T0/T0] * 100) were correlated with RT administration, Objective Response Rate (ORR) and Progression-free survival (PFS). Results Among 57 patients, 22 underwent RT either before (RTpre, 32%) or during (RTpost, 68%) IO. RT doses ranged from 8 to 54 Gy according to sites of involvement. No significant differences in IO response and survival emerged between RT and RTnull cases. Compared to RTnull, baseline RTpre immune profiles exhibited increased % of CD8, CD19, CD14 and NK cells expressing PD1, reduced CD4+GZB/Perf+ and Tregs. Delta variation revealed that RTpre attenuated the downregulation of PD1 in CD8, CD4 and CD19 cells following IO, and favored the circulating release of GZB/Perf+ CD8 and CD4. RTpost reduced CD8 number, proliferation and PD1 expression, while increasing NKT. At variance from RTpre, RTpost did not affect PD1+ T cell kinetic, although decreased total and PD1+ NKs. We observed a clear trend towards prolonged PFS in RTpre group (median PFS: RTpre= not reached, RTpost= 7.1 mos, RTnull= 5.9 mos) associated with slightly increased ORR, hinting that the positive cytotoxic (CD8+GZB/Perf+, NK) to suppressive (Tregs) balance triggered by RTpre may result in greater benefit from IO. Conclusions RT timing may differentially impact on clinical outcome of IO-treated NSCLC patients by shaping immune cells phenotypes and dynamics.
238P Exploring blood immune cell dynamics to unravel the immunomodulatory effect of radiotherapy in NSCLC patients undergoing immune checkpoint inhibitors / Mazzaschi, G.; Tamarozzi, P.; Lorusso, B.; Verzè, M.; Pluchino, M.; Trentini, F.; Dalla Valle, B.; Minari, R.; Perrone, F.; Bordi, P.; Leonetti, A.; Moron Dalla Tor, L.; Leo, L.; Milanese, G.; Balbi, M.; Buti, S.; Roti, G.; Quaini, F.; Sverzellati, N.; Tiseo, M.. - In: IMMUNO-ONCOLOGY TECHNOLOGY. - ISSN 2590-0188. - 16:(2022), p. 100227. [10.1016/j.iotech.2022.100227]
238P Exploring blood immune cell dynamics to unravel the immunomodulatory effect of radiotherapy in NSCLC patients undergoing immune checkpoint inhibitors
Mazzaschi, G.
;Lorusso, B.;Trentini, F.;Leonetti, A.;Moron Dalla Tor, L.;Leo, L.;Milanese, G.;Balbi, M.;Buti, S.;Roti, G.;Quaini, F.;Sverzellati, N.;Tiseo, M.
2022-01-01
Abstract
Background The role of radiotherapy (RT) in immunotherapy-based (IO) combinatory approaches to advanced NSCLC is still uncertain due to its dual immune -suppressive and -stimulatory effect. We performed a longitudinal peripheral blood (PB) analysis to determine whether RT, by affecting immune cell phenotypes and dynamics, impacts on clinical outcome of IO-treated NSCLC patients. Methods PB samples were prospectively collected at baseline (T0) and first disease assessment (T1) on stage IV NSCLC undergoing 1st line IO-based regimens alone (RTnull) or combined with RT (RTpre, within 4 weeks before IO; RTpost, during IO). Flow cytometric analysis included CD3, CD8, CD4, NK, NKT, CD19, CD14 and Treg cells, expression of functional molecules (PD1, Granzyme B [GZB], Perforin [Perf]) and proliferative index (Ki67). PB parameters and their delta variation ([T1-T0/T0] * 100) were correlated with RT administration, Objective Response Rate (ORR) and Progression-free survival (PFS). Results Among 57 patients, 22 underwent RT either before (RTpre, 32%) or during (RTpost, 68%) IO. RT doses ranged from 8 to 54 Gy according to sites of involvement. No significant differences in IO response and survival emerged between RT and RTnull cases. Compared to RTnull, baseline RTpre immune profiles exhibited increased % of CD8, CD19, CD14 and NK cells expressing PD1, reduced CD4+GZB/Perf+ and Tregs. Delta variation revealed that RTpre attenuated the downregulation of PD1 in CD8, CD4 and CD19 cells following IO, and favored the circulating release of GZB/Perf+ CD8 and CD4. RTpost reduced CD8 number, proliferation and PD1 expression, while increasing NKT. At variance from RTpre, RTpost did not affect PD1+ T cell kinetic, although decreased total and PD1+ NKs. We observed a clear trend towards prolonged PFS in RTpre group (median PFS: RTpre= not reached, RTpost= 7.1 mos, RTnull= 5.9 mos) associated with slightly increased ORR, hinting that the positive cytotoxic (CD8+GZB/Perf+, NK) to suppressive (Tregs) balance triggered by RTpre may result in greater benefit from IO. Conclusions RT timing may differentially impact on clinical outcome of IO-treated NSCLC patients by shaping immune cells phenotypes and dynamics.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
