Regulatory T Cells Poise the Myeloid Landscape after Chemotherapy in Lung Tumors

Tumor-associated macrophages (TAM) and regulatory T cells (Treg) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. Although Tregs are well known for their immunosuppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. In this study, we have shown that in human and mouse lung cancer, chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward not only a proinflammatory signature but also an increased TGFβ-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation, demonstrating that Tregs dampen the proinflammatory status of the MP compartment induced by chemotherapy and promote tumor relapse. Anti-TNFR2 antibody treatment during the Treg recovery phase affected the direct interaction between Tregs and MPs, increased the proinflammatory signature of the MPs, and improved survival in the mouse model. Targeting the cross-talk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome.