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Background <p>Immunotherapy (IO) has improved prognosis of non-small cell lung cancer (NSCLC); however, some patients experience primary IO resistance (PIR). CXCL13 could be a promising PIR biomarker due to its role in antitumor immune responses.</p> Methods <p>177 patients with stage IV NSCLC receiving IO from the observational, multicenter, real-world study BLI-O were included from 15 centers in Spain. CXCL13 and 39 other cytokines were measured in 158 baseline (BS1) and 98 post-first-cycle of IO (BS2) plasma samples. Additionally, peripheral T and B cell BS2 immunophenotypes were determined. CXCL13 levels were also measured in plasma samples from 38 stage IIIA 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.</p> Results <p>Metastatic PIR patients had higher CXCL13 plasma levels compared to non-PIR patients, especially in BS2 samples, and exhibited a greater increase of CXCL13 levels after the first cycle of IO. Patients with high BS2 CXCL13 levels showed shorter PFS (<i>p</i> = 0.0002) and OS (<i>p</i> = 0.0007). Females showed a lower percentage of high CXCL13 cases compared to male cases. CXCL13 did not influence the growth of NSCLC cell lines in vitro. Moreover, the expression of the CXCL13/CXCR5 axis was restricted to the immune compartment of tumors. Plasmatic CXCL13 levels were not associated with PD-L1 TPS expression nor TLS density in tumor tissue. However, at systemic level, patients with high CXCL13 levels exhibited impaired B and T cell phenotypes, along with elevated levels of inflammatory cytokines, after first IO cycle. Finally, high BS2 CXCL13 levels in resectable cases were also associated with PIR.</p> Conclusions <p>Elevated CXCL13 levels after the first cycle of IO are associated with PIR and an altered peripheral immune profile in NSCLC, supporting its potential as a prognostic biomarker in these patients.</p>

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Plasmatic CXCL13 as a biomarker of primary resistance to immunotherapy and impaired peripheral immunity in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Marta Molina-Alejandre,
  • Cristina Martínez-Toledo,
  • Belén Sierra-Rodero,
  • Virginia Calvo,
  • Ana Collazo-Lorduy,
  • Pilar Diz-Tain,
  • Silvia Sequero-Lopez,
  • Sergio Vázquez Estévez,
  • Xabier Mielgo,
  • Natividad Martinez-Banaclocha,
  • Jose Luís González-Larriba,
  • Alfredo Sánchez-Hernández,
  • Anna Estival,
  • Juan Coves Sarto,
  • Ernest Nadal,
  • Reyes Bernabé,
  • Santiago Ponce-Aix,
  • Aránzazu García-Grande,
  • Soledad Medina-Valdivieso,
  • Elisa Mañas-Mora,
  • Elena Moreno-Alonso,
  • Ángeles Gil-González,
  • Juan Manuel Gutiérrez-Escobedo,
  • Silvia Peña-Cabia,
  • Diego Megías,
  • Mariola Blanco,
  • Alberto Cruz-Bermúdez,
  • Mariano Provencio

摘要

Background

Immunotherapy (IO) has improved prognosis of non-small cell lung cancer (NSCLC); however, some patients experience primary IO resistance (PIR). CXCL13 could be a promising PIR biomarker due to its role in antitumor immune responses.

Methods

177 patients with stage IV NSCLC receiving IO from the observational, multicenter, real-world study BLI-O were included from 15 centers in Spain. CXCL13 and 39 other cytokines were measured in 158 baseline (BS1) and 98 post-first-cycle of IO (BS2) plasma samples. Additionally, peripheral T and B cell BS2 immunophenotypes were determined. CXCL13 levels were also measured in plasma samples from 38 stage IIIA 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 had higher CXCL13 plasma levels compared to non-PIR patients, especially in BS2 samples, and exhibited a greater increase of CXCL13 levels after the first cycle of IO. Patients with high BS2 CXCL13 levels showed shorter PFS (p = 0.0002) and OS (p = 0.0007). Females showed a lower percentage of high CXCL13 cases compared to male cases. CXCL13 did not influence the growth of NSCLC cell lines in vitro. Moreover, the expression of the CXCL13/CXCR5 axis was restricted to the immune compartment of tumors. Plasmatic CXCL13 levels were not associated with PD-L1 TPS expression nor TLS density in tumor tissue. However, at systemic level, patients with high CXCL13 levels exhibited impaired B and T cell phenotypes, along with elevated levels of inflammatory cytokines, after first IO cycle. Finally, high BS2 CXCL13 levels in resectable cases were also associated with PIR.

Conclusions

Elevated CXCL13 levels after the first cycle of IO are associated with PIR and an altered peripheral immune profile in NSCLC, supporting its potential as a prognostic biomarker in these patients.