IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity.
Document Type
Article
Publication Date
7-2-2024
Original Citation
Wei J,
Mayberry C,
Lv X,
Hu F,
Khan T,
Logan N,
Wilson J,
Sears J,
Chaussabel D,
Chang C.
IL3-Driven T Cell-Basophil Crosstalk Enhances Antitumor Immunity. Cancer Immunol Res. 2024;12(7):822-39.
Keywords
JMG, JGM, SS1, Animals, Mice, Mice, Knockout, T-Lymphocytes, Cytotoxic, Interleukin-3, Mice, Inbred C57BL, Cell Line, Tumor, Tumor Microenvironment, Neoplasms, Cell Communication, Humans
JAX Source
Cancer Immunol Res. 2024;12(7):822-39.
ISSN
2326-6074
PMID
38739030
DOI
https://doi.org/10.1158/2326-6066.CIR-23-0851
Grant
We thank the funding support of New Investigator, Fast Forward Award, and Pilot Projects funds from The JAX Cancer Center Support Grant (P30CA034196), JAX Director’s Innovation Fund (19000-21-07), the American Cancer Society Research Grant (IRG-16-191-33), the V Foundation (V2021- 036), the AAI Careers in Immunology Fellowship Program, the Pyewacket Fund, the National Natural Science Foundation of China (82371753), the Science Fund for Excellent Young Scholars of Shandong Province (2023HWYQ-036), the TaiShan Scholars (tsqn202312082), and the Natural Science Foundation of Shandong Province (ZR2023MH163)
Abstract
Cytotoxic T lymphocytes (CTL) are pivotal in combating cancer, yet their efficacy is often hindered by the immunosuppressive tumor microenvironment, resulting in CTL exhaustion. This study investigates the role of interleukin-3 (IL3) in orchestrating antitumor immunity through CTL modulation. We found that intratumoral CTLs exhibited a progressive decline in IL3 production, which was correlated with impaired cytotoxic function. Augmenting IL3 supplementation, through intraperitoneal administration of recombinant IL3, IL3-expressing tumor cells, or IL3-engineered CD8+ T cells, conferred protection against tumor progression, concomitant with increased CTL activity. CTLs were critical for this therapeutic efficacy as IL3 demonstrated no impact on tumor growth in Rag1 knockout mice or following CD8+ T-cell depletion. Rather than acting directly, CTL-derived IL3 exerted its influence on basophils, concomitantly amplifying antitumor immunity within CTLs. Introducing IL3-activated basophils retarded tumor progression, whereas basophil depletion diminished the effectiveness of IL3 supplementation. Furthermore, IL3 prompted basophils to produce IL4, which subsequently elevated CTL IFNγ production and viability. Further, the importance of basophil-derived IL4 was evident from the absence of benefits of IL3 supplementation in IL4 knockout tumor-bearing mice. Overall, this research has unveiled a role for IL3-mediated CTL-basophil cross-talk in regulating antitumor immunity and suggests harnessing IL3 sustenance as a promising approach for optimizing and enhancing cancer immunotherapy. See related Spotlight, p. 798.