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. 2025 Apr 14;31(8):1533-1545.
doi: 10.1158/1078-0432.CCR-24-1926.

Longitudinal Blood Immune-Inflammatory and Radiomic Profiling to Decode Different Patterns of Acquired Resistance to Immunotherapy in Patients with NSCLC

Giulia Mazzaschi #  1   2 , Cristina Marrocchio #  2   3 , Lucas Moron Dalla Tor  2 , Ludovica Leo  2 , Maurizio Balbi  4 , Gianluca Milanese  2   3 , Ganiyat A R Adebanjo  2   3 , Bruno Lorusso  2 , Gregorio Monica  5 , Monica Pluchino  1 , Roberta Minari  1 , Simona D'Agnelli  1 , Elisa Cardinale  1   2 , Fabiana Perrone  1 , Paola Bordi  1 , Alessandro Leonetti  1 , Roberta E Ledda  2   3 , Mario Silva  2   3 , Sebastiano Buti  1   2 , Giovanni Roti  2   5   6 , Stefano Bettati  2 , Federico Quaini  2 , Marcello Tiseo #  1   2 , Nicola Sverzellati #  2   3
Affiliations

Longitudinal Blood Immune-Inflammatory and Radiomic Profiling to Decode Different Patterns of Acquired Resistance to Immunotherapy in Patients with NSCLC

Giulia Mazzaschi et al. Clin Cancer Res. .

Abstract

Purpose: To uncover the underpinnings of acquired resistance (AR) to immunotherapy (IO), we determined whether distinctive clinicopathologic, radiomic, and peripheral blood (PB) immune-inflammatory 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 IO-treated 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 top-ranked 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. See related commentary by Jeng and Schoenfeld, p. 1381.

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