# 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.

## Key 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.