Regulatory T cells poise the myeloid landscape after chemotherapy in lung tumors

Tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) are major immune components of the tumor microenvironment, promoting tumor growth and limiting the efficacy of chemotherapy in almost all cancer indications. While Tregs are well known for their immune suppressive activity toward the adaptive immune system, less is known about their regulatory activity toward the innate compartment. We showed in human and mouse lung cancer, that chemotherapy transiently reduced Treg number and switched the mononuclear phagocyte (MP) landscape toward a pro-inflammatory signature but also an increased TGFß-expressing TAM accumulation over time. Preventing Treg recovery further increased the recruitment of monocytes and limited TGFß expression upon TAM differentiation, demonstrating that Tregs dampen the pro-inflammatory 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 pro-inflammatory signature of the MPs and improved survival in the mouse model. Targeting the crosstalk between tumor-associated Tregs and the MP compartment limits the reconstitution of an anti-inflammatory environment following chemotherapy and improves therapeutic outcome. Overall design: Four sorted tumor samples, each pooled from three mice with multifocal lung tumors, were analyzed: untreated (NT), chemotherapy-treated (CP), chemotherapy plus anti-TNFR2-treated (CP_aTNFRII) and local irradiation (IR). The samples include T lymphocyte and myeloid cell populations, analyzed using scRNA-seq.