A Multidimensional Analysis of the Impact of Obesity on Immune Checkpoint Inhibitor Therapy Efficacy

Rheumatology and Immunology Oncology Life Sciences Immunology Medicine
obesity immune checkpoint inhibitors inflammation survival rate cancer

Background and Research Motivation

Obesity has been identified as an important risk factor for various malignancies. It not only promotes the growth and spread of tumor cells but also leads to generally poorer prognosis in patients. However, recent research has found that obese patients receiving immune checkpoint inhibitors (ICI) therapy, especially under certain tumor types and gender conditions, show an unusual survival benefit, known as the “Obesity Paradox.” This phenomenon indicates that the survival rate of obese patients after receiving ICI treatment is higher than that of patients with normal or lower body weight. Although this paradox has been initially confirmed, many factors still affect its effectiveness, including tumor type, patient’s gender, and degree of obesity. In view of this, Wenjing Xu and others conducted a multi-dimensional retrospective study to analyze the impact of obesity on the efficacy of ICI treatment, aiming to provide new scientific evidence for the “Obesity Paradox.”

This study was jointly completed by the research team from the Oncology Department of Guangdong Provincial People’s Hospital and related medical institutions. The article was published in 2024 in “Cancer Cell International,” providing new insights into the influence of obesity on the efficacy of immunotherapy.

Research Methods and Experimental Design

This retrospective study analyzed the data of 224 patients who received ICI treatment from June 2019 to August 2023. The study used Slice-O-Matic software to automatically segment patients’ skeletal muscle, subcutaneous fat, and visceral fat, and calculated the skeletal muscle index (SMI), subcutaneous fat index (SFI), and visceral fat index (VFI). In addition, the neutrophil-to-lymphocyte ratio (NLR) was used as a systemic inflammatory marker to analyze its relationship with overall survival (OS) and progression-free survival (PFS). The study mainly used univariate and multivariate Cox regression analyses to verify the association between BMI, body composition parameters, NLR, and survival prognosis.

Research Process and Data Analysis

  1. Data Collection and Sample Grouping: The study collected basic data including patient age, gender, BMI, tumor type, and ICI treatment regimen. Patients were divided into underweight, normal weight, overweight, and obese groups according to BMI classification standards. BMI was recalculated at the first ICI treatment to analyze its change on survival impact.

  2. Imaging Analysis and Obesity Index Calculation: Abdominal CT images were used to evaluate the body composition of the patients, including the area size of SM, VAT, and SAT. The body composition parameters that cannot be evaluated by BMI were calculated based on the L3 vertebral level’s cross-sectional area. To ensure the accuracy of the results, image analysis was completed by an experienced radiology researcher.

  3. Survival Analysis: Kaplan-Meier survival analysis and Log-rank test were used to group analyze BMI, VFI, SFI, SMI, and NLR to determine their impact on survival rates. The study found that the OS of obese patients, especially those with more visceral fat accumulation, was significantly extended after receiving ICI treatment (Log-rank p=0.027).

  4. Multivariate Analysis: Through multivariate Cox regression analysis, the role of NLR as an independent prognostic factor was explored. The results showed that high NLR was significantly related to poorer OS (HR=1.036, 95% CI: 0.996 to 1.078; p=0.002), while VFI was related to better OS (HR=0.436, 95% CI 0.198–0.963; p=0.040).

Research Results and Findings

  1. Positive Association between Obesity and ICI Efficacy: The OS of obese patients was significantly extended after ICI treatment. Patients with a BMI higher than the normal value had a longer survival period at the first ICI treatment, and the overweight and obese patient groups showed significant survival benefits over the underweight group (Log-rank p=0.027).

  2. Gender Differences: The ICI efficacy was more significant in obese male patients, with extended OS, whereas female obese patients did not show a significant survival difference. The influence of gender on ICI efficacy might be related to fat distribution and sex hormone differences, for example, visceral fat accumulation is more in males, and it contains more inflammatory factors and immune cells, which may significantly impact ICI efficacy.

  3. Impact of Fat Distribution: Patients with high VFI had significantly extended OS, while SFI did not show obvious correlation, suggesting that visceral fat might be an important indicator of prognosis in obese patients. The distribution and action differences of different types of fat in the body may affect the tumor’s immune microenvironment.

  4. Role of Systemic Inflammation Indicator (NLR): Patients with lower NLR significantly extended OS after ICI treatment, especially in males and patients treated with Camrelizumab. High NLR predicts poorer prognosis, indicating that NLR might serve as an independent prognostic factor in obese patients with potential to predict ICI efficacy.

  5. Limitations of Peripheral Blood Cell Counts: The study failed to demonstrate a direct association between peripheral blood neutrophil or lymphocyte counts and obesity-related chronic inflammation, likely because obesity-related chronic inflammation is mainly induced by macrophages accumulated in adipose tissue. This further indicates the limitations of peripheral blood tests in reflecting the body’s chronic inflammation status.

Significance and Value of the Study

This study validates the scientific nature of the “Obesity Paradox” under certain conditions, revealing the potential for obesity, gender, fat distribution, and NLR to predict the efficacy of ICI treatment, especially highlighting the possible survival advantage of obese males in ICI treatment. Additionally, for the first time, the study combined VFI and NLR for the efficacy prediction of ICI treatment in obese patients, providing important biological evidence and potential therapeutic targets. This offers more precise body composition indicators for clinical assessment of obese patients’ prognosis where BMI is insufficient.

Highlights and Innovations of the Study

  1. Innovative Multi-dimensional Analysis Method: The study comprehensively analyzed the impact of obesity on ICI treatment efficacy, combining BMI, VFI, SFI, and NLR, providing a comprehensive prognostic assessment framework.

  2. First Focus on Gender Differences: This study is one of the few that reveals the impact of gender on the “Obesity Paradox,” emphasizing the significant benefits obese male patients gain in ICI treatment.

  3. NLR as an Independent Prognostic Factor: The study supports NLR as an independent predictive factor of prognosis in obese patients, suggesting systemic inflammation related to obesity may be a crucial determinant of ICI efficacy.

Research Limitations and Outlook

The study is a single-center retrospective analysis with a limited sample size, mainly focusing on gastrointestinal cancer patients. Future studies need to verify the findings in larger sample sizes and multiple cancer types. Moreover, the impact of obesity on ICI efficacy changes over time, indicating the necessity to assess ICI efficacy at different time points. Based on the study results, reasonable dietary interventions may further optimize ICI therapeutic effect, providing a new perspective for personalized management and lifestyle adjustments in obese patients.

This research provides new scientific support for the “Obesity Paradox,” unveiling the complex role mechanisms of obesity, gender, and systemic inflammation in immunotherapy. It offers critical clinical insights for future tumor patients’ weight management and the evaluation of immunotherapy efficacy.