Purpose: To uncover the underpinnings of acquired resistance (AR) to immunotherapy (IO), we determined whether distinctive clinicopathologic, radiomic, and peripheral blood (PB) immuneinflammatory features reflect oligo- and systemic (sys)-AR in patients with advanced non–small cell lung cancer (NSCLC) undergoing immune checkpoint inhibitor therapy. Experimental Design: On 105 consecutive patients with IOtreated advanced NSCLC, PB immunophenotypes, cytokines, and CT-derived radiomic features (RF), extracted from primary and merged metastatic lesions, were prospectively collected at baseline (T0) and at the first disease assessment (T1, 9–12 weeks), and their Δ variation [(T1�T0)/T0] was computed. AR, defined as progression after the initial response (complete/partial) or stable disease ≥6 months, was subdivided according to the number of new and/or progressive lesions in oligoAR (≤3) and sysAR (>3). Clinicopathologic, PB, and radiomic parameters and survival outcomes were statistically correlated to AR patterns. Results: OligoAR and sysAR involved 24% and 12.4% of cases, respectively. Whereas baseline PB immune profiles were comparable, a Δpos cytotoxic (NK, CD8+granzyme B+) and Δneg immunosuppressive (CD14+ monocytes) dynamic coupled with different modulations of IL-6, TGF-β1, TNFα, and soluble PD-L1 represented distinctive features of oligoAR versus sysAR (P < 0.05). Significantly longer postprogression survival characterized oligoAR versus sysAR (median 20.3 vs. 5.6 months; HR, 0.22; P < 0.001). The number and sites of oligoAR involvement appeared to condition the blood immune background (P < 0.05) and survival. ΔRFs outperformed baseline RFs, with 15 ΔRFs sharply discriminating oligoAR from sysAR (P range: <0.001– 0.04). ROC analysis confirmed the optimal performance of topranked ΔRFs (AUC range: 0.88–0.99). Conclusions: Longitudinal analysis of blood-immune hallmarks and radiomic descriptors may decipher distinct patterns of AR to IO in advanced patients with NSCLC.
Longitudinal blood immune-inflammatory and radiomic profiling to decode different patterns acquired resistance to immunotherapy in patients with NSCLC / Mazzaschi, G; Marrocchio, C; Moron Dalla Tor, L; Leo, L; Balbi, M; Milanese, G; Adebanjio, G. A. R.; Lorusso, B; Monica, G; Pluchino, M; Minari, R; D'Agnelli, S; Cardinale, E; Perrone, F; Bordi, P; Leonetti, A; Ledda, R. E.; Silva, M; Buti, S; Roti, G; Bettati, S; Quaini, F; Tiseo, M; Sverzellati, N. - In: CLINICAL CANCER RESEARCH. - ISSN 1078-0432. - 31:8(2025), pp. 1533-1545. [10.1158/1078-0432.CCR-24-1926]
Longitudinal blood immune-inflammatory and radiomic profiling to decode different patterns acquired resistance to immunotherapy in patients with NSCLC
Mazzaschi G
;Marrocchio C;Moron Dalla Tor L;Leo L;Milanese G;Lorusso B;Monica G;Pluchino M;Minari R;D'Agnelli S;Cardinale E;Bordi P;Leonetti A;Ledda R. E;Silva M;Buti S;Roti G;Bettati S;Quaini F;Tiseo M;Sverzellati N
2025-01-01
Abstract
Purpose: To uncover the underpinnings of acquired resistance (AR) to immunotherapy (IO), we determined whether distinctive clinicopathologic, radiomic, and peripheral blood (PB) immuneinflammatory features reflect oligo- and systemic (sys)-AR in patients with advanced non–small cell lung cancer (NSCLC) undergoing immune checkpoint inhibitor therapy. Experimental Design: On 105 consecutive patients with IOtreated advanced NSCLC, PB immunophenotypes, cytokines, and CT-derived radiomic features (RF), extracted from primary and merged metastatic lesions, were prospectively collected at baseline (T0) and at the first disease assessment (T1, 9–12 weeks), and their Δ variation [(T1�T0)/T0] was computed. AR, defined as progression after the initial response (complete/partial) or stable disease ≥6 months, was subdivided according to the number of new and/or progressive lesions in oligoAR (≤3) and sysAR (>3). Clinicopathologic, PB, and radiomic parameters and survival outcomes were statistically correlated to AR patterns. Results: OligoAR and sysAR involved 24% and 12.4% of cases, respectively. Whereas baseline PB immune profiles were comparable, a Δpos cytotoxic (NK, CD8+granzyme B+) and Δneg immunosuppressive (CD14+ monocytes) dynamic coupled with different modulations of IL-6, TGF-β1, TNFα, and soluble PD-L1 represented distinctive features of oligoAR versus sysAR (P < 0.05). Significantly longer postprogression survival characterized oligoAR versus sysAR (median 20.3 vs. 5.6 months; HR, 0.22; P < 0.001). The number and sites of oligoAR involvement appeared to condition the blood immune background (P < 0.05) and survival. ΔRFs outperformed baseline RFs, with 15 ΔRFs sharply discriminating oligoAR from sysAR (P range: <0.001– 0.04). ROC analysis confirmed the optimal performance of topranked ΔRFs (AUC range: 0.88–0.99). Conclusions: Longitudinal analysis of blood-immune hallmarks and radiomic descriptors may decipher distinct patterns of AR to IO in advanced patients with NSCLC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
