IFNγ-driven suppression of alternative NF-κB by activated CTLs selectively induces CTL- but not Treg-attraction in the tumor microenvironment 2673

Abstract Description Recruitment of intratumoral CD8+ cytotoxic T cells (CTLs) predicts improved outcomes in cancer patients, but the transient character of CTL effector function and regulatory T cell (Treg) influx limit long-term survival. Activated CTLs induce immunosuppression that self-limits antitumor immunity through the release of TNFα and IFNγ which activate COX2/PGE2 in myeloid-derived suppressor cells. To investigate if secondary suppression also involves chemoattraction of Tregs, we tested if activated CTLs modulate chemokine production in the tumor microenvironment (TME). Unexpectedly, CTLs selectively induced CTL-attracting chemokines CCL5 and CXCL10 but not Treg-attracting CCL22 in ovarian cancer ascites. CTL-sourced TNFα and IFNγ synergistically induced CTL attractants by TME-resident myeloid cells and monocyte-derived macrophages that resulted in selective recruitment of CTLs without Tregs. TNFα-driven induction of CCL5 and IFNγ-driven induction of CXCL10 required canonical but not alternative NF-κB signaling. In contrast, the induction of CCL22 required both canonical and alternative NF-κB. Selective production of CTL- and not Treg-attracting chemokines resulted from suppression of alternative NF-κB signaling by IFNγ. Our data indicate that activated CTLs not only kill tumor cells but also reprogram NF-κB-regulated chemokine production and selectively promote recruitment of additional effector cells, thus indicating new opportunities for enhancing cancer therapies. Funding Sources Suppoprted by NIH PO132714; NIH P50CA159981; NIH 5P01CA234212; NCI T32 Training Grant T32CA085183; the 2015 CRI Clinical Strategy Team Grant; NIH Shared Instrument Grant 1S10OD018048. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)