Regulatory T cells in lung tumor shape an anti-inflammatory myeloid-landscape recovery after chemotherapy

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 transformed the myeloid landscape of the tumor microenvironment, inducing a transient monocyte accumulation and exhibiting a stronger pro-inflammatory signature along with increased TGFβ expression. Prevent Treg recovery further increased the recruitment of monocytes and limited TGFβ expression upon TAM differentiation arguing for a role of Tregs in the anti-inflammatory polarization of the myeloid compartment. Using anti-TNFR2, to target preferentially tumor-infiltrating Treg, affected their recruitment and dynamic of interaction with myeloid cells into the tumor. This was associated with a sustained pro-inflammatory signature of the myeloid cells and improved survival in the mouse model. Chemo-immunotherapy targeting the cross-talk between tumor-associated Tregs and myeloid compartments may provide alternative or complementary benefit in the context of immune-checkpoint blockade therapies.