Deciphering the different patterns of acquired resistance in immunotherapy treated NSCLC patients through an integrated clinical and blood immuneinflammatory profiling

Background: Clinical and biological patterns of acquired resistance (AR) to Immune Checkpoint Inhibitors (ICIs) and the relative optimal management are still poorly understood. Thus, we determined whether distinctive clinicopathological and peripheral blood (PB) immuneinflammatory features might reflect oligo and systemic (sys) AR in advanced NSCLC patients undergoing ICIs. Materials and Methods: On PB collected at baseline (T0) and first disease assessment (T1) from 105 ICI-treated NSCLC, we prospectively assessed LDH, derived Neutrophil-to-Lymphocyte ratio (dNLR), LIPI score, relevant immunophenotypes (flow-cytometry) and their respective delta (D) variation [(T1-T0)/T0*100]. AR, defined as progression after initial response (CR/PR/SD ⩾ 6 mos.), was subdivided according to the number of new and/or progressive lesions in oligoAR (⩽ 3) and sysAR (> 3). Initial PD or SD < 6 mos. embodied non responders (NR), while absence of progression or PFS ⩾ 12 mos. enclosed long-term/not progressors (LT/NP). Clinicopathological, PB parameters and survival outcome were statistically evaluated according to AR pattern. Results: OligoAR was present in 24% of cases, while sysAR in 12.4%, both mainly involving extracranial (89%) sites. Compared to NR, oligoAR pattern was associated with significantly lower T0 and D LDH, dNLR and LIPI, whereas no differences were observed vs sysAR and LT/NP. While baseline PB immune profiles were comparable, a D positive cytotoxic (NK, NKT, CD8+Ki67+, CD8+Gnz+) and D negative immunosuppressive (CD14+ monocytes, CD4+CD25+FOXP3+ Tregs) dynamic were distinctive features of oligoAR vs sysAR (P<0.05). Conversely, compared to LT/NP, oligoAR cases showed a lower cytotoxic/proliferating CD8 response coupled with higher CD14+/Tregs feedback (P<0.05). Within oligoAR, patients with 1 progressive lesion, compared to those with ⩾ 2, exhibited baseline lower LDH and higher NK/CD8+Gnz+ cytotoxic cells (P<0.05) which in turn conditioned longer OS (median OS not reached vs 17.4 mos.; HR: 4.90, 95% CI 0.90-7.92; P=0.04). Importantly, despite similar clinical profile, prolonged post-progression survival characterized oligoAR vs sysAR (median OS not reached vs 11.3 mos.; HR: 0.21, 95% CI: 0.08-0.59; P=0.001). Conclusions: The longitudinal analysis of blood immune hallmarks merged with clinicopathological characteristics may decode the distinct patterns of AR to ICIs in NSCLC patients.