Correlation Between Oxidative Stress and Immune Profiles During Immunotherapy in Metastatic Non-Oncogene-Addicted NSCLC Patients

Oxidative stress is considered one of the cancer hallmarks, influencing tumor initiation, progression, and metastasis. High levels of reactive oxygen species (ROS) impair the effectiveness of the immune response in cancer patients. We examined changes in oxidative stress during immunotherapy, exploring the relationship between the immune system and clinical parameters related to oxidative burden. Several T-cell and myeloid subsets from 79 metastatic non-oncogene-addicted non-small-cell lung cancer (NSCLC) patients were analyzed using flow cytometry. Additionally, 20 cytokines were measured in serum samples, and sNox2-dp levels, an indicator of NOX2 activity, were assessed by ELISA. Seventy-nine healthy donors served as controls. The data showed that cancer patients had higher levels of sNox2-dp compared to healthy donors (<i>p</i> < 0.0001). Elevated sNox2-dp levels were associated with inflammation-related comorbidities (<i>p</i> = 0.008) and platelet counts (<i>p</i> = 0.03) in NSCLC patients. Furthermore, sNox2-dp displayed a negative correlation with immune cells involved in activation, such as proliferating (Ki67⁺) CD8⁺, PD1⁺ and effector lymphocytes, and a positive correlation with immunosuppressive PMN-MDSCs and inflammatory soluble immune factors, including IL1α, IL1β, IL6, IL10, CCL3, and CCL4. Oxidation levels decreased after immunotherapy (<i>p</i> = 0.04) and increased only in non-responder patients (<i>p</i> = 0.02). Oxidative stress may be indirectly affected by immunotherapy and could serve as a novel tool to identify responding patients in the NSCLC setting.