IL-1 receptor–associated kinase-3 acts as an immune checkpoint in myeloid cells to limit cancer immunotherapy
Gürcan Tunalı, … , Irineos Papakyriacou, Yumeng Mao
Gürcan Tunalı, … , Irineos Papakyriacou, Yumeng Mao
Published February 9, 2023
Citation Information: J Clin Invest. 2023;133(7):e161084. https://doi.org/10.1172/JCI161084.
View: Text | PDF
Research Article Immunology Oncology Article has an altmetric score of 2

IL-1 receptor–associated kinase-3 acts as an immune checkpoint in myeloid cells to limit cancer immunotherapy

Abstract

Inflammatory mediators released by cancer cells promote the induction of immune suppression and tolerance in myeloid cells. IL-1 receptor–associated kinase-3 (IRAK3) is a pseudokinase that inhibits IL-1/TLR signaling, but its role in patients treated with immune checkpoint blockade (ICB) therapy remains unclear. Using RNA-Seq data from the IMvigor210 trial, we found that tumors with high IRAK3 expressions showed enriched antiinflammatory pathways and worse clinical response to ICB therapy. Upon IRAK3 protein deletion with CRISPR/Cas9, primary human monocytes displayed altered global protein expression and phosphorylation in quantitative proteomics and released more proinflammatory cytokines in response to stimulation. Bone marrow–derived macrophages from an IRAK3 CRISPR KO mouse model demonstrated a proinflammatory phenotype and enhanced sensitivity to TLR agonists compared with WT cells. IRAK3 deficiency delayed the growth of carcinogen-induced and oncogene-driven murine cancer cells and induced enhanced activation in myeloid cells and T cells. Upon ICB treatment, IRAK3-KO mice showed enrichment of TCF1+PD-1+ stem-like memory CD8+ T cells and resulted in superior growth inhibition of immunologically cold tumors in vivo. Altogether, our study demonstrated what we believe to be a novel cancer-driven immune tolerance program controlled by IRAK3 in humans and mice and proposed its suitability as an immunotherapy target.

Authors

Gürcan Tunalı, Marta Rúbies Bedós, Divya Nagarajan, Patrik Fridh, Irineos Papakyriacou, Yumeng Mao

×

Figure 7

ICB treatment induces distinct immunological changes in IRAK3 KO mice.

Options: View larger image (or click on image) Download as PowerPoint
ICB treatment induces distinct immunological changes in IRAK3 KO mice. (...
(A) MYCN-amplified 9464D murine neuroblastoma cells were injected s.c. in WT or IRAK3-KO mice. Group sizes were indicated in the figures. When tumors were measureable in 80% of the mice, 200 μg anti-PD-1 antibody (clone RMP1-14) or a Rat IgG2a isotype control antibody was infused i.p. in 100 μL PBS per mouse on days 20, 24, and 28 in WT or IRAK3-KO mice. Tumor growth of individual mice and tumor volume distribution at the study endpoint were shown. Frequencies of the (B) TCF1+PD-1+ stem-like CD8+ T cells or (C) CD11c+MHCII+ myeloid cells were shown in treatment groups in the tumors or in the spleens. (D and E) PD-1 blockade–sensitive EO771 cancer cells (400,000 cells per mouse) were injected s.c. in WT and IRAK3-KO mice, followed by treatment with the PD-1 blocking antibody or the Rat IgG2a isotype control antibody on days 11, 14, and 17. Tumor volumes and immunological changes in the spleens at the study endpoint were shown. All studies used age-matched female WT or IRAK3-KO mice. Statistical tests were performed using unpaired t tests and P values were shown on the figures.