{Reference Type}: Journal Article
{Title}: Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy.
{Author}: Geels SN;Moshensky A;Sousa RS;Murat C;Bustos MA;Walker BL;Singh R;Harbour SN;Gutierrez G;Hwang M;Mempel TR;Weaver CT;Nie Q;Hoon DSB;Ganesan AK;Othy S;Marangoni F;
{Journal}: Cancer Cell
{Volume}: 42
{Issue}: 6
{Year}: 2024 Jun 10
{Factor}: 38.585
{DOI}: 10.1016/j.ccell.2024.05.013
{Abstract}: PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.