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Background Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, often diagnosed at advanced stages. While immunotherapy (IO) targeting the PD-1/PD-L1 axis has improved survival, some patients experience primary IO resistance (PIR). 1 2 In this sense, CXCL13 could be a promising PIR biomarker due to its role in antitumor immune responses.3 Methods This study included 177 patients with advanced NSCLC receiving IO from the BLI-O study. CXCL13 and 39 other cytokines were measured in 158 baseline (BS1) and 98 post-first-cycle (BS2) plasma samples. Peripheral T- and B-cell immunophenotypes were assessed by flow cytometry in 83 and 30 blood samples, respectively. Additionally, CXCL13 levels were measured in 35 BS2 plasma samples from resectable locally advanced NSCLC patients treated with neoadjuvant chemoimmunotherapy from the NADIM II trial ( NCT03838159). PIR was defined as disease progression within 3 months in non-surgical cases or incomplete pathological response in surgical cases.Results Metastatic PIR patients (41 cases, 23.2%) had higher BS1 CXCL13 levels compared to non-PIR patients (136 cases, 76.8%) (p=0.042), being this more evident in BS2 samples (p=0.0002). Furthermore, PIR patients exhibited a greater increase of CXCL13 levels after the first cycle of IO (p=0.037). Patients with High BS2 CXCL13 levels (65 cases, 66.3%) were associated with significantly shorter PFS (HR=2.25, p=0.0002) and OS (HR=2.32, p=0.0007), compared to low CXLC13 cases (33, 33.7%). The prognostic value of BS2 CXCL13 levels was independent of IO combination, line, ECOG and sex. However, stratifying by sex, females showed a higher percentage of low CXCL13 cases (p=0.039) compared to male cases ( figure 1).Regarding peripheral immune status at BS2 (figure 2), CXCL13 high patients showed impaired B-cell profiles, including a decreased percentage of transitional B-cells, a reduced expression of CD24 and CD38 in naïve B-cells cells, and lower percentage of memory B-cells with lower CD27 expression compared to CXCL13 low patients. Additionally, they exhibited reduced percentages of CD8+CD28+ T cells and CD8+CD62L+, and showed elevated levels of inflammatory cytokines (e.g., IFN-γ, IL-1a, G-CSF).Finally, higher BS2 CXCL13 levels in potentially resectable neoadjuvant IO cases were associated with PIR (p=0.005). Patients with ≥311pg/mL in BS2 samples showed 72.7% of PIR compared to 22.2% in patients with <311pg/mL (p=0.007).Conclusions Elevated CXCL13 levels after the first cycle of immunotherapy are associated with Primary IO Resistance (PIR) in metastatic and locally advanced NSCLC, as well as with a weakened peripheral immune profile, supporting its potential as a prognostic biomarker in these patients.Trial Registration NADIM II ClinicalTrials.gov number, NCT03838159References Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. New England Journal of Medicine 2016;375:1823–33.Provencio M, Nadal E, González-Larriba JL, et al. Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer. New England Journal of Medicine 2023;389:504–13.Gu X, Li D, Wu P, et al. Revisiting the CXCL13/CXCR5 axis in the tumor microenvironment in the era of single-cell omics: Implications for immunotherapy. Cancer Lett. Elsevier Ireland Ltd; 2024.Ethics Approval The study was conducted in accordance with the precepts of the Code of Ethics of the World Medical Association (Declaration of Helsinki).Consent Written informed consent was obtained from the patient for publication of this abstract and any accompanying images.Abstract 755 Figure 1Abstract 755 Figure 2