Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer

Abstract

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.

Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity

“…In aggregate, our mechanistic observations indicate that the curative activity of CTX-471 requires not only the presence of CD137-expressing innate and adaptive immune effectors, but also the presence of FcγR-expressing cells. This codependency provides a good explanation for the tumor-selective activity of CTX-471, as the frequency of both CD137 + TILs and macrophages that constitutively express FcγRs have been shown to be higher within tumors as compared with normal tissues (41)(42)(43)(44).…”

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

“…TAMs display a remarkable plasticity to environmental cues. Indeed, in the early state of tumor, TAMs display mostly monocyte/M1 phenotype, whereas at later stages, TAMs mostly belong to the M2 phenotype [28][29][30] . While M1 macrophages are pro-inflammatory, they have anti-tumoral effects, associated with cytotoxicity towards cancer cells, and immune-stimulatory functions 30 .…”

Identification of an Immune-related Seven-lncRNA Signature Predicting Prognosis and Tumor-infiltrating Immune Cells in Lung Adenocarcinoma

“…Macrophages originate from monocytes of bloodstream and becoming TAMs after migration. TAMs drive disease to deteriorate via promoting cancer metastasis in early-stage lung cancer [39]. LncRNAs participate in the development and polarization of macrophages, which might showed big impact on cancer progression and the e cacy of PD-L1 antibody [36].…”