238P - Exploring blood immune cell dynamics to unravel the immunomodulatory effect of radiotherapy in NSCLC patients undergoing immune checkpoint inhibitors

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 (RT^null) or combined with RT (RT^pre, within 4 weeks before IO; RT^post, 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 (RT^pre, 32%) or during (RT^post, 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 RT^null cases. Compared to RT^null, baseline RT^pre immune profiles exhibited increased % of CD8, CD19, CD14 and NK cells expressing PD1, reduced CD4+GZB/Perf+ and Tregs. Delta variation revealed that RT^pre attenuated the downregulation of PD1 in CD8, CD4 and CD19 cells following IO, and favored the circulating release of GZB/Perf+ CD8 and CD4. RT^post reduced CD8 number, proliferation and PD1 expression, while increasing NKT. At variance from RT^pre, RT^post did not affect PD1+ T cell kinetic, although decreased total and PD1+ NKs. We observed a clear trend towards prolonged PFS in RT^pre group (median PFS: RT^pre= not reached, RT^post= 7.1 mos, RT^null= 5.9 mos) associated with slightly increased ORR, hinting that the positive cytotoxic (CD8+GZB/Perf+, NK) to suppressive (Tregs) balance triggered by RT^pre 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.

Legal entity responsible for the study

University Hospital of Parma.

Funding

Associazione Italiana per la Ricerca sul Cancro (AIRC).

Disclosure

All authors have declared no conflicts of interest.