IFNγ-mediated suppression of alternative NF-κB in tumor-resident myeloid cells promotes selective recruitment of cytotoxic but not regulatory T cells

TL;DR

This study shows how T cells can selectively attract other immune cells to tumors, potentially improving cancer immunotherapy.

Contribution

The novel finding is that IFNγ suppresses alternative NF-κB in myeloid cells, promoting cytotoxic T cell recruitment while inhibiting regulatory T cells.

Findings

Activated CTLs induce chemokines that attract cytotoxic T cells but not Tregs in ovarian cancer TME.

IFNγ suppresses alternative NF-κB signaling in myeloid cells, reducing CCL22 and favoring CTL recruitment.

Regulation of NF-κB signaling by T cells offers new strategies to enhance immunotherapy outcomes.

Abstract

Immunotherapy is currently effective in less than half of patients with solid tumors, and most responders develop secondary progression. High infiltration of the tumor microenvironment (TME) with CD8+ cytotoxic T cells (CTLs) and low infiltration with regulatory T cells (Treg) predicts the patients’ responses to immunotherapy and long-term outcomes. To identify the mechanisms regulating long-term stability of CTL infiltration, we analyzed the impact of CTL-produced cytokines on the TME by co-culturing patient-isolated ascites cells with activated T cells. Unexpectedly, we observed that activated CTLs selectively induce cytotoxic T cell-attracting chemokines but not chemokines that attract T regulatory cells in ovarian cancer TME and tumor-associated myeloid cells, resulting in recruitment of additional CTLs without Tregs. This selectivity resulted from the unique dependence of CCL22 induction on both canonical and alternative NF-κB and the suppression of alternative NF-κB signaling by T cell-released IFNγ. Our data demonstrate that T cell-produced IFNγ suppresses alternative NF-κB signaling in TME-associated myeloid cells, allowing for the induction of CTL-attracting chemokines with the concomitant suppression of Treg-attracting CCL22. These novel functions of IFNγ and activated T cells in regulating the balance between canonical and alternative NF-κB signaling in myeloid cells provide new opportunities to enhance and stabilize the selective CTL influx in the TME.

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