ASA - Exercise Reprograms Adiposity-Induced Immune Dysfunction in NSCLC and Non-Tumor Bearing Lungs - Implications for Lung Cancer Therapy and Interception

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Exercise Reprograms Adiposity-Induced Immune Dysfunction in NSCLC and Non-Tumor Bearing Lungs - Implications for Lung Cancer Therapy and Interception
*Randall J. Smith^¹, *Akhil Pachimatla^¹, *Kayleigh Erickson^², *Deschana Washington^³, *Robert Zollo^³, *Yeshwanth Vedire^¹, *Mary Reid^⁴, *Mark Hennon^¹, *Nathaniel Ivanick^¹, *Joseph Barbi^³, *Andrew Ray^², Sai Yendamuri^¹
^¹Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York; ^²Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York; ^³Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York; ^⁴Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York

Objectives:
Excess adiposity drives systemic immune dysfunction and promotes lung cancer progression by impairing effector cell function and expanding suppressive populations. Identifying modifiable factors that reverse these effects may enable interceptive strategies. Physical activity improves metabolic and inflammatory profiles, but its effects on adiposity-associated immune dysregulation remain incompletely understood. We hypothesized that exercise reverses obesity-specific immune suppression in the lung and tumor microenvironment while restoring effector T cell function.
Methods:
Mice with diet-induced obesity (DIO) and normal-weight controls were housed under sedentary conditions or given voluntary access to exercise wheels. Flow cytometry assessed Tregs, CD8+ T cells, and MDSCs in lungs, other immune tissues, and tumors of Lewis Lung Carcinoma (LLC)-implanted mice. RNA sequencing (RNA-seq) was performed on whole tumors to evaluate obesity- and exercise-associated transcriptional programs. Tumor-naïve DIO and lean mice were also analyzed to determine baseline lung and immune-tissue phenotypes. Human bronchoalveolar lavage (BAL) samples (n = 74) from cancer-free lobes were analyzed using spectral flow cytometry and stratified by total fat area (TFA) and self-reported activity (≥60 min/week). Analyses adjusted for age, sex, smoking, and cancer diagnosis.
Results:
In DIO mice, high adiposity increased Treg frequency and PD-1 expression, elevated Treg:CD8+ ratios, and expanded GR1+ MDSCs in tumors. PD-L1 was elevated on tumor-associated MDSCs, while CD8+ infiltration, activation (PD-1+Ki-67+), and cytokine production (IFNγ, TNFα) were reduced. Obese tumors contained more non-proliferative PD-1+Ki-67- CD8+ cells and a higher PD-1+ effector Treg:CD8+ ratio. Exercise reversed these obesity-specific effects, reducing PD-1+ Tregs, MDSCs, and PD-L1 while restoring CD8+ infiltration, activation, and cytokine production. RNA-seq showed obesity induced inflammatory and extracellular matrix remodeling programs, whereas exercise shifted tumors toward normalized metabolic, vascular, and transcriptional profiles. In tumor-naïve DIO mice, obesity elevated PD-1+ Tregs, GR1+ MDSCs, PD-L1, and suppressed CD8+ function in the lung; exercise normalized these changes. In human BAL, high-TFA participants had increased Tregs, PD-1+ Tregs, MDSCs, and a higher PD-1+ effector Treg:CD8+ ratio. Those reporting ≥60 min/week activity showed reduced PD-1+ Tregs and MDSCs and normalized immune ratios.
Conclusions:
Exercise reverses high adiposity-associated immune suppression, restores immune balance, and enhances antitumor responses through modulation of PD-1+ Tregs, MDSCs, and CD8+ effector function. For the first time, we show these effects are adiposity-specific and most pronounced in the lung. Therefore, physical activity represents a clinically accessible interception strategy capable of reshaping the tumor-promoting immune environment in lung and potentially other cancers.

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