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PD-L1+ tumor cells, but not macrophages, are likely responsible for inhibiting tumor-specific T cells in early-stage human lung tumors. In defense of tumor-associated macrophages: Although preclinical models using implanted tumors in mice are valuable, they cannot completely recapitulate the early stages of natural tumor development in humans. To better understand how monocytes and macrophages influence developing tumor immunity, Singhal et al. studied samples from patients with early-stage lung cancer. They phenotyped monocytes and macrophages in tumors and adjacent tissue, as well as samples from control subjects without cancer. The authors found that, although tumor-associated macrophages expressed PD-L1, these cells did not generally suppress T cell responses. Their results suggest that tumor-associated macrophages should not be assumed to be protumorigenic, especially during early stages of cancer. Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs). The TAMs coexpressed M1/M2 markers, as well as T cell coinhibitory and costimulatory receptors. Functionally, TAMs did not primarily suppress tumor-specific effector T cell responses, whereas tumor monocytes tended to be more T cell inhibitory. TAMs expressing relevant MHC class I/tumor peptide complexes were able to activate cognate effector T cells. Mechanistically, programmed death-ligand 1 (PD-L1) expressed on bystander TAMs, as opposed to PD-L1 expressed on tumor cells, did not inhibit interactions between tumor-specific T cells and tumor targets. TAM-derived PD-L1 exerted a regulatory role only during the interaction of TAMs presenting relevant peptides with cognate effector T cells and thus may limit excessive activation of T cells and protect TAMs from killing by these T cells. These results suggest that the function of TAMs as primarily immunosuppressive cells might not fully apply to early-stage human lung cancer and might explain why some patients with strong PD-L1 positivity fail to respond to PD-L1 therapy. [ABSTRACT FROM AUTHOR]