期刊
JCI INSIGHT
卷 3, 期 11, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.120626
关键词
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资金
- Cambridge Trust
- Karus Therapeutics Ltd.
- Biotechnology and Biological Sciences Research Council (BBSRC) [BBS/E/B/000C0407, BBS/E/B/000-C0409, BBS/E/B/000-C0427, BBS/E/B/000-C0428, BB/N007794/1]
- Wellcome Trust [105663/Z/14/Z, 095198/Z/10/Z]
- BBSRC [BBS/E/B/000C0407, BB/N007794/1, BBS/E/B/000C0409, BB/E009867/1, BBS/E/B/000C0427, BBS/E/B/000C0428] Funding Source: UKRI
- MRC [1947452] Funding Source: UKRI
- Wellcome Trust [095198/Z/10/Z] Funding Source: Wellcome Trust
Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase delta (PI3K delta) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3K delta inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3K delta inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3K delta inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression. Compared with Treg-specific PI3K delta deletion, systemic PI3K delta inactivation is less effective at conferring resistance to tumors. We show that PI3K delta deficiency impairs the maturation and reduces the capacity of CD8(+) cytotoxic T lymphocytes (CTLs) to kill tumor cells in vitro, and to respond to tumor antigen-specific immunization in vivo. PI3K delta inactivation antagonized the antitumor effects of tumor vaccines and checkpoint blockade therapies intended to boost the CD8(+) T cell response. These findings provide insights into mechanisms by which PI3K delta inhibition promotes antitumor immunity and demonstrate that the mechanism is distinct from that mediated by immune checkpoint blockade.
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