Mazzaschi Giulia, Marrocchio Cristina, Moron Dalla Tor Lucas, Leo Ludovica, Balbi Maurizio, Milanese Gianluca, Adebanjo Ganiyat A R, Lorusso Bruno, Monica Gregorio, Pluchino Monica, Minari Roberta, D'Agnelli Simona, Cardinale Elisa, Perrone Fabiana, Bordi Paola, Leonetti Alessandro, Ledda Roberta E, Silva Mario, Buti Sebastiano, Roti Giovanni, Bettati Stefano, Quaini Federico, Tiseo Marcello, Sverzellati Nicola
Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
Department of Medicine and Surgery, University of Parma, Parma, Italy.
Clin Cancer Res. 2025 Apr 14;31(8):1533-1545. doi: 10.1158/1078-0432.CCR-24-1926.
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.
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.
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).
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.
为了揭示获得性免疫治疗（IO）耐药（AR）的潜在机制，我们确定了独特的临床病理、影像组学和外周血（PB）免疫炎症特征是否能反映接受免疫检查点抑制剂治疗的晚期非小细胞肺癌（NSCLC）患者的寡转移和全身转移（sys）AR。
对105例连续接受IO治疗的晚期NSCLC患者，前瞻性收集基线（T0）和首次疾病评估（T1，9 - 12周）时从原发性和合并的转移病灶中提取的PB免疫表型、细胞因子和CT衍生的影像组学特征（RF），并计算其Δ变化[（T1 - T0）/T0]。AR定义为初始缓解（完全/部分）或疾病稳定≥6个月后的进展，根据寡转移AR（≤3个）和全身转移AR（>3个）中新发和/或进展性病灶的数量进行细分。临床病理、PB和影像组学参数以及生存结果与AR模式进行统计学关联。
寡转移AR和全身转移AR分别涉及24%和12.4%的病例。虽然基线PB免疫谱具有可比性，但Δ阳性细胞毒性（NK，CD8 +颗粒酶B +）和Δ阴性免疫抑制（CD14 +单核细胞）动态变化以及IL - 6、TGF - β1、TNFα和可溶性PD - L1的不同调节代表了寡转移AR与全身转移AR的独特特征（P < 0.05）。寡转移AR与全身转移AR相比，进展后生存期显著更长（中位生存期20.3个月对5.6个月；HR，0.22；P < 0.001）。寡转移AR累及的数量和部位似乎影响血液免疫背景（P < 0.05）和生存期。ΔRFs优于基线RFs，15个ΔRFs能显著区分寡转移AR与全身转移AR（P范围：<0.001 - 0.04）。ROC分析证实了排名靠前的ΔRFs的最佳性能（AUC范围：0.88 - 0.99）。
对血液免疫特征和影像组学描述符的纵向分析可能有助于解读晚期NSCLC患者对IO的不同AR模式。见Jeng和Schoenfeld的相关评论，第1381页。
