Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer PMID: 37366231

ADC Targets in Oncology

2026-04-10

Plasma fractalkine contributes to systemic myeloid diversity and PD-L1/PD-1 blockade in lung cancer

EMBO Rep. 2023 Jun 27;e55884. doi: 10.15252/embr.202255884.

Ana Bocanegra ^# ¹ , Gonzalo Fernández-Hinojal ² , Daniel Ajona ³ ⁴ ⁵ , Ester Blanco ¹ ⁶ , Miren Zuazo ¹ , Maider Garnica ¹ , Luisa Chocarro ¹ , Elvira Alfaro-Arnedo ⁷ , Sergio Piñeiro-Hermida ¹ , Pilar Morente ¹ , Leticia Fernández ¹ , Ana Remirez ³ , Miriam Echaide ¹ , Maite Martinez-Aguillo ⁸ , Idoia Morilla ⁸ , Beatriz Tavira ³ ⁹ ¹⁰ , Alejandra Roncero ¹¹ ¹² , Carolina Gotera ¹³ , Alfonso Ventura ¹⁴ , Nerea Recalde ¹⁴ , José G Pichel ⁷ ¹⁵ , Juan José Lasarte ⁹ ¹⁶ , Luis Montuenga ³ ⁴ ¹⁰ , Ruth Vera ⁸ , Ruben Pio ³ ⁴ ⁵ , David Escors ^# ¹ , Grazyna Kochan ^# ¹

Affiliations

1. Oncoimmunology Group, Navarrabiomed, Hospital Universitario de Navarra, Universidad Publica de Navarra (UPNA), IdISNA, Pamplona, Spain.
2. Medical Oncology Department, Clinica Universidad de Navarra, Madrid, Spain.
3. Program in Solid Tumors, CIMA-University of Navarre-IdISNA, Pamplona, Spain.
4. CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, Madrid, Spain.
5. Department of Biochemistry and Genetics, School of Sciences, University of Navarra-IdISNA, Pamplona, Spain.
6. Program in Gene Therapy and Regulation of Gene Expression, CIMA-University of Navarra-IdISNA, Pamplona, Spain.
7. Lung Cancer and Respiratory Diseases Unit, Center for Biomedical Research of La Rioja (CIBIR), Fundación Rioja Salud, Logroño, Spain.
8. Department of Oncology, Hospital Universitario de Navarra-IdISNA, Pamplona, Spain.
9. Cancer Center University of Navarra (CCUN), Pamplona, Spain.
10. Department of Pathology, Anatomy and Physiology, School of Medicine, University of Navarra-IdISNA, Pamplona, Spain.
11. Pathological Anatomy Service, Hospital Universitario San Pedro, Rioja Salud, Logroño, Spain.
12. Pneumology Service, Rioja Salud, Logroño, Spain.
13. Fundación Jiménez Díaz, Madrid, Spain.
14. Centro de Salud Salazar-Ezcároz, Navarra, Spain.
15. Spanish Biomedical Research Networking Centre, CIBERES, Madrid, Spain.
16. Program in Immunology and Immunotherapy, CIMA-University of Navarra-IdISNA, Pamplona, Spain.
# Contributed equally.

Abstract

Recent studies highlight the importance of baseline functional immunity for immune checkpoint blockade therapies. High-dimensional systemic immune profiling is performed in a cohort of non-small-cell lung Cancer patients undergoing PD-L1/PD-1 blockade immunotherapy. Responders show high baseline myeloid phenotypic diversity in peripheral blood. To quantify it, we define a diversity index as a potential biomarker of response. This parameter correlates with elevated activated monocytic cells and decreased granulocytic phenotypes. High-throughput profiling of soluble factors in plasma identifies fractalkine (FKN), a chemokine involved in immune chemotaxis and adhesion, as a biomarker of response to immunotherapy that also correlates with myeloid cell diversity in human patients and murine models. Secreted FKN inhibits lung adenocarcinoma growth in vivo through a prominent contribution of systemic effector NK cells and increased tumor immune infiltration. FKN sensitizes murine lung Cancer models refractory to anti-PD-1 treatment to immune checkpoint blockade immunotherapy. Importantly, recombinant FKN and tumor-expressed FKN are efficacious in delaying tumor growth in vivo locally and systemically, indicating a potential therapeutic use of FKN in combination with immunotherapy.

Keywords

NK cells; adenocarcinoma; biomarker; monocytes; neutrophils.