Immune composition and adenosine-associated transcription in non-small-cell lung cancer after neoadjuvant PD-1 blockade.

IF 3.5 Q3 Medicine Cancer treatment and research communications Pub Date : 2026-10-22 DOI:10.1016/j.ctarc.2026.101499

Li-Zhen Chen, Run-Nan Chen, Guolin Alexander Wen

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Abstract

Background: In non-small-cell lung cancer (NSCLC), high metabolic gene expression during immunotherapy can reflect either more infiltrating cells or altered cellular activity. We tested whether separating cell abundance from cell-intrinsic transcription clarifies incomplete tumour clearance after neoadjuvant programmed cell death-1 (PD-1) blockade.

Methods: Using cross-dataset triangulation, we analysed 1173,843 post-treatment immune cells from 224 patients (103 non-major pathological response [non-MPR], 40 major response, and 81 complete response) via patient-level regressions adjusted for clinical covariates, cell proportions, and library size. Findings were compared across recurrence follow-up (n = 154), spatial profiling (n = 40), three bulk cohorts (n = 78), population data (n = 3045), and 7224 genetic tests.

Results: Non-MPR tumours had higher regulatory T-cell (Treg) proportions (+3.91% FOXP3+, +3.07% CCR8+) and elevated lymphoid glycolysis, exhaustion, Treg, and adenosine scores (all false-discovery rate q ≤ 1.09 × 10^-7). Notably, adjusting for cell composition and depth abolished broad glycolysis and exhaustion differences, whereas adenosine-associated transcription persisted (difference 0.044, 95% confidence interval [CI] 0.020-0.068; q = 0.0046), peaking in terminally exhausted CD8+ T cells (0.449, 95% CI 0.328-0.571; q = 1.29 × 10^-10). Paired spatial biopsies localized HK2, LDHB, and SLC16A1 to tumour regions (q ≤ 0.0057) and CTLA4 to stroma (q = 5.14 × 10^-5) without response interactions. A six-component score discriminated non-MPR (apparent area under the curve [AUC] 0.791, 95% CI 0.724-0.851) and recurrence (hazard ratio 1.41, 95% CI 1.04-1.93), attenuating after pathology adjustment, but failed in pre-treatment bulk cohorts (AUCs 0.091-0.517); no genetic test passed correction (q ≥ 0.9934).

Conclusions: Incomplete response involves Treg accumulation and cell-intrinsic adenosine transcription, offering exploratory, hypothesis-generating insights for prospective validation.

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新辅助PD-1阻断后非小细胞肺癌的免疫组成和腺苷相关转录

背景：在非小细胞肺癌（NSCLC）中，免疫治疗期间高代谢基因表达可以反映细胞浸润性增加或细胞活性改变。我们测试了将细胞丰度与细胞内在转录分离是否能澄清新辅助程序性细胞死亡-1 （PD-1）阻断后的不完全肿瘤清除。方法：采用交叉数据集三角形分析，通过患者水平回归调整临床共变量、细胞比例和文库大小，分析了来自224例患者的1173,843个治疗后免疫细胞（103个非主要病理反应[非mpr]， 40个主要反应和81个完全反应）。研究结果在复发随访（n = 154）、空间分析（n = 40）、三个批量队列（n = 78）、人群数据（n = 3045）和7224个基因检测之间进行比较。结果：非mpr肿瘤具有更高的调节性t细胞（Treg）比例（+3.91% FOXP3+, +3.07% CCR8+），淋巴糖酵解、衰竭、Treg和腺苷评分升高（所有错误发现率q ≤ 1.09 × 10-7）。值得注意的是，调整细胞组成和深度消除了广泛的糖酵解和衰竭差异，而腺苷相关转录持续存在（差异0.044,95%可信区间[CI] 0.020-0.068; q = 0.0046），在终末衰竭的CD8+ T细胞中达到峰值（0.449,95% CI 0.328-0.571; q = 1.29 × 10-10）。配对空间活检将HK2， LDHB和SLC16A1定位于肿瘤区域（q ≤ 0.0057），CTLA4定位于基质（q = 5.14 × 10-5），没有反应相互作用。六组分评分区分非mpr（曲线下表观面积[AUC] 0.791, 95% CI 0.724-0.851）和复发率（风险比1.41,95% CI 1.04-1.93），在病理调整后减弱，但在治疗前的大量队列中失败（AUC 0.091-0.517）；没有基因检测通过校正（q ≥ 0.9934）。结论：不完全应答涉及Treg积累和细胞内在腺苷转录，为前瞻性验证提供了探索性的、假设生成的见解。

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来源期刊

Cancer treatment and research communications Medicine-Oncology

CiteScore

4.30

自引率

0.00%

发文量

148

审稿时长

56 days

期刊介绍： Cancer Treatment and Research Communications is an international peer-reviewed publication dedicated to providing comprehensive basic, translational, and clinical oncology research. The journal is devoted to articles on detection, diagnosis, prevention, policy, and treatment of cancer and provides a global forum for the nurturing and development of future generations of oncology scientists. Cancer Treatment and Research Communications publishes comprehensive reviews and original studies describing various aspects of basic through clinical research of all tumor types. The journal also accepts clinical studies in oncology, with an emphasis on prospective early phase clinical trials. Specific areas of interest include basic, translational, and clinical research and mechanistic approaches; cancer biology; molecular carcinogenesis; genetics and genomics; stem cell and developmental biology; immunology; molecular and cellular oncology; systems biology; drug sensitivity and resistance; gene and antisense therapy; pathology, markers, and prognostic indicators; chemoprevention strategies; multimodality therapy; cancer policy; and integration of various approaches. Our mission is to be the premier source of relevant information through promoting excellence in research and facilitating the timely translation of that science to health care and clinical practice.