A therapeutically actionable pro-tumoral axis of cytokines involving interleukin-8, TNFa and IL-1B
Irene Olivera 1 , Rebeca Sanz-Pamplona 2 , Elixabet Bolanos 3 , Inmaculada Rodriguez 3 , Inaki Etxeberria 4 , Assunta Cirella 5 , Josune Egea 6 , Saray Garasa 7 , Itziar Migueliz 1 , Inaki Eguren-Santamaria 8 , Miguel F Sanmamed 9 , Javier Glez-Vaz 1 , Arantza Azpilikueta 5 , Maite Alvarez 10 , Maria C Ochoa 11 , Beatrice Malacrida 12 , David Propper 12 , Carlos E de Andrea 13 , Pedro Berraondo 14 , Frances R Balkwill 12 , Alvaro Teijeira 5 , Ignacio Melero 5
Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL-8 mRNA levels correlate with IL-1B and TNFa transcripts.
Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon-carcinoma organoids and fresh human tumor explants. Although IL-8 is absent from the mouse genome, a similar murine axis in which TNFa and IL-1B upregulate CXCL1 and CXCL2 in tumor cells was revealed.
Furthermore, intratumoral injection of TNFa and IL-1B induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFa-blockers infliximab and etanercept, or the IL-1B inhibitor anakinra were able to interfere with this pathogenic cytokine loop.
Finally, in paired plasma samples of cancer patients undergoing TNFa blockade with infliximab in a clinical-trial, reductions of circulating IL-8 were substantiated.