肿瘤细胞治疗研究
英文原题：Circulating immune cell profiling in advanced cervical and endometrial cancer patients treated with PD-1 blockade, radiotherapy, and immune modulation in the PRIMMO trial.
Circulating immune cell profiling in advanced cervical and endometrial cancer patients treated with PD-1 blockade, radiotherapy, and immune modulation in the PRIMMO trial.
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纵向免疫变化，而非单纯的基线差异，可区分应答者与非应答者。
免疫检查点阻断（ICB）已革新包括妇科肿瘤在内的癌症治疗，但只有部分患者获得持久应答。为提高疗效，ICB越来越多地与其他互补治疗联合。组织生物标志物虽可提供有价值的信息，但具有侵入性，且无法反映全身免疫变化，限制了其应用。外周血是一种无创替代样本，但接受ICB方案治疗的晚期宫颈癌（CC）和子宫内膜癌（EC）患者的免疫细胞谱尚未得到充分研究。
本探索性转化研究分析PRIMMO临床试验（ClinicalTrials.gov：NCT03192059）中晚期CC（n=19）和EC（n=24）患者的血液免疫谱。患者接受基于ICB的方案治疗，在入组时（基线）、治疗期间（第7周）及治疗后（第26周，或疾病较早进展时于第26周前）采集外周血。采用多色流式细胞术和ELISA检测免疫细胞亚群及选定的全身免疫介质。
基线时，CTLA-4⁺ PD-1⁺ CD4⁺ T细胞和CD161⁺ CD56⁺ CD16⁺ NK细胞仅与生存结局相关，而综合免疫评分同时与治疗应答和生存结局相关。治疗期间，应答者在治疗早期和晚期时间点的免疫谱相对稳定。相反，未应答者的pDC持续减少，T细胞各亚群中的活化标志物（CD69、CD137、HLA-DR）及共刺激/抑制标志物（CTLA-4、ICOS、Tim-3）持续升高，且早期和晚期均可见共表达。NK细胞亚群也表现出活化特征增加（CD69、CD161、HLA-DR）。这些变化伴有免疫调节细胞群扩增，包括按表型标志物界定的髓源性抑制细胞（MDSC）和调节性T细胞（Treg），犬尿氨酸/色氨酸比值升高以及可溶性PD-1（sPD-1）增加。按肿瘤类型分析提示，CC中NK细胞相关变化相对更多，EC中T细胞相关变化相对更多。
纵向免疫变化比单纯基线差异更能区分应答者和未应答者。联合治疗未应答并非表现为免疫活动不足，而是与活化和调节性免疫特征持续且协调地增强相关，提示治疗后全身免疫失衡。这些结果支持未来临床试验采用纵向、整合性的免疫监测策略。
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, including gynecological cancers, yet durable responses are observed only in subsets of patients. To improve efficacy, ICB is increasingly combined with complementary approaches. Although tissue-based biomarkers provide valuable information, their invasiveness and inability to capture systemic immune changes limit their utility. Peripheral blood offers a noninvasive alternative, but immune cell profiling in advanced cervical cancer (CC) and endometrial (EC) patients receiving ICB-based therapy remain underexplored.
This exploratory translational study of the PRIMMO clinical trial (https://clinicaltrials.gov/search?id=%22NCT03192059%22) analyzed blood-based immune profiles from advanced CC (n=19) and EC (n=24) patients treated with an ICB-based regimen. Peripheral blood was collected at inclusion (baseline), on-treatment (week 7), and post-treatment (week 26 or earlier (< week 26) in case of earlier disease progression). Immune cell subsets and selected systemic immune mediators were assessed by multicolor flow cytometry and ELISA.
At baseline, CTLA-4 + PD-1 + CD4 + T cells and CD161 + CD56 + CD16 + NK cells were associated with survival outcomes only, while the combined immune score was associated with both treatment response and survival outcomes. During treatment, responders exhibited relatively stable immune profiles at both early and late treatment time points. In contrast, non-responders showed sustained decreases in pDCs and increases in activation (CD69, CD137, HLA-DR) and co-stimulatory/inhibitory markers (CTLA-4, ICOS, Tim-3) across T cell subsets, including co-expression at both early and late phases of treatment. NK cell subsets also displayed increased activation features (CD69, CD161, HLA-DR). These changes were accompanied by expansion of immunoregulatory populations (MDSCs and Tregs), quantified based on phenotypic markers only, along with an increased kynurenine/tryptophan ratio, and elevated sPD-1 levels. Tumor-type-specific analyses suggested relatively more NK-related changes in CC and T cell-related changes in EC.
Longitudinal immune changes, rather than baseline differences alone, distinguished responders from non-responders. Non-response to the combination treatment is not characterized by immune inactivity but rather associated with sustained and coordinated increases in both activation and regulatory immune features, suggesting a shift toward systemic immune imbalance following treatment. These findings support the need for longitudinal, integrative immune monitoring strategies in future clinical trials.
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