Nonclassical monocytes potentiate anti-tumoral CD8⁺ T cell responses in the lungs

CD8⁺ T cells drive anti-cancer immunity in response to antigen-presenting cells such as dendritic cells and subpopulations of monocytes and macrophages. While CD14⁺ classical monocytes modulate CD8⁺ T cell responses, the contributions of CD16⁺ nonclassical monocytes to this process remain unclear. Herein we explored the role of nonclassical monocytes in CD8⁺ T cell activation by utilizing E2-deficient (E2^-/-) mice that lack nonclassical monocytes. During early metastatic seeding, modeled by B16F10-OVA cancer cells injected into E2^-/- mice, we noted lower CD8⁺ effector memory and effector T cell frequencies within the lungs as well as in lung-draining mediastinal lymph nodes in the E2^-/- mice. Analysis of the myeloid compartment revealed that these changes were associated with depletion of MHC-II^loLy6C^lo nonclassical monocytes within these tissues, with little change in other monocyte or macrophage populations. Additionally, nonclassical monocytes preferentially trafficked to primary tumor sites in the lungs, rather than to the lung-draining lymph nodes, and did not cross-present antigen to CD8⁺ T cells. Examination of the lung microenvironment in E2^-/- mice revealed reduced CCL21 expression in endothelial cells, which is chemokine involved in T cell trafficking. Our results highlight the previously unappreciated importance of nonclassical monocytes in shaping the tumor microenvironment via CCL21 production and CD8⁺ T cell recruitment.