Alden Stephanie L, Charmsaz Soren, Li Howard L, Tsai Hua-Ling, Danilova Ludmila, Munjal Kabeer, Brancati Madelena, Warner Aanika, Howe Kathryn, Griffin Ervin, Nakazawa Mari, Thoburn Chris, Gizzi Jennifer, Hernandez Alexei, Gross Nicole E, Coyne Erin M, Hallab Elsa, Shin Sarah S, Durham Jennifer, Lipson Evan J, Ged Yasser, Baretti Marina, Hoffman-Censits Jean, Seiwert Tanguy Y, Guha Aditi, Bansal Sanjay, Tang Laura, Chandler G Scott, Mohindra Rajat, Garonce-Hediger Rachel, Jaffee Elizabeth M, Ho Won Jin, Kao Chester, Yarchoan Mark
The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA.
J Immunother Cancer. 2025 Jan 19;13(1):e009734. doi: 10.1136/jitc-2024-009734.
Obesity is a risk factor for developing cancer but is also associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs), a phenomenon called the obesity paradox. To interrogate mechanisms of divergent immune responses in obese and non-obese patients, we examined the relationship among obesity status, clinical responses, and immune profiles from a diverse, pan-tumor cohort of patients treated with ICI-based therapy.
From June 2021 to March 2023, we prospectively collected serial peripheral blood samples from patients with advanced or metastatic solid tumors who received ICI as standard of care at Johns Hopkins. Patients were stratified by obesity status at treatment initiation, with obesity defined as body mass index (BMI)≥30 at treatment initiation and BMI≥18.5 and <30 considered non-obese; underweight patients (BMI<18.5) were excluded. We evaluated the concentration of 37 cytokines and used cytometry by time of flight to characterize immune cell clusters and cell-surface expression markers at baseline and on-treatment.
We enrolled 94 patients, of whom 30 (32%) were obese and 64 (68%) were non-obese. Compared with non-obese patients, obese patients had superior progression-free survival (HR: 0.44 (95% CI: 0.24 to 0.81), p=0.01) and overall survival (OS) (HR: 0.24 (95% CI: 0.07 to 0.80), p=0.02). Obese patients had lower serum IL-15 levels at treatment baseline and lower on-treatment levels of IL-6, IL-8, and IL-15. Low on-treatment IL-6 was associated with improved OS (HR: 0.27 (95% CI: 0.08 to 0.88), p=0.03), as was low on-treatment IL-8 (HR: 0.19 (95% CI: 0.05 to 0.70), p=0.01). Obese patients demonstrated lower levels of T effector cells with reduced expression of cytotoxicity markers and higher expression of exhaustion markers at baseline and on-treatment.
Obese and non-obese patients with cancer have divergent immunological responses to ICIs. Obesity is associated with reduced levels of certain inhibitory cytokines and higher expression of T-cell exhaustion markers. ICI-based therapy may more effectively reverse T-cell dysfunction in obese patients, potentially contributing to the paradoxically improved responses in this population.
肥胖是患癌的一个风险因素，但也与免疫检查点抑制剂（ICI）治疗后改善的预后相关，这一现象被称为肥胖悖论。为了探究肥胖和非肥胖患者免疫反应差异的机制，我们在一个接受基于ICI治疗的多肿瘤队列患者中，研究了肥胖状态、临床反应和免疫特征之间的关系。
2021年6月至2023年3月，我们前瞻性地收集了约翰霍普金斯医院接受ICI作为标准治疗的晚期或转移性实体瘤患者的系列外周血样本。患者在治疗开始时按肥胖状态分层，肥胖定义为治疗开始时体重指数（BMI）≥30，BMI≥18.5且<30为非肥胖；排除体重过轻患者（BMI<18.5）。我们评估了37种细胞因子的浓度，并使用飞行时间流式细胞术来表征基线和治疗期间的免疫细胞簇及细胞表面表达标志物。
我们纳入了94例患者，其中30例（32%）肥胖，64例（68%）非肥胖。与非肥胖患者相比，肥胖患者的无进展生存期更好（HR：0.44（95%CI：0.24至0.81），p = 0.01），总生存期（OS）也更好（HR：0.24（95%CI：0.07至0.80），p = 0.02）。肥胖患者治疗基线时血清IL-15水平较低，治疗期间IL-6、IL-8和IL-15水平也较低。治疗期间低水平的IL-6与改善的OS相关（HR：0.27（95%CI：0.08至0.88），p = 0.03），治疗期间低水平的IL-8也是如此（HR：0.19（95%CI：0.05至0.70），p = 0.01）。肥胖患者在基线和治疗期间表现出较低水平的T效应细胞，其细胞毒性标志物表达降低，耗竭标志物表达升高。
肥胖和非肥胖癌症患者对ICI有不同的免疫反应。肥胖与某些抑制性细胞因子水平降低和T细胞耗竭标志物表达升高有关。基于ICI的治疗可能更有效地逆转肥胖患者的T细胞功能障碍，这可能是该人群反应改善的原因。
