Tumor-derived exosomal HMGB1 promotes esophageal squamous cell carcinoma progression through inducing PD1 TAM expansion.

Macrophages constitute one of the most common components of immune cells, which penetrate tumors and they have a key role in tumor prognosis. Here, we identified an unrecognized macrophage subpopulation, which favors tumorigenesis. These macrophages express programmed cell death protein 1 (PD1) in a constitutive manner and accumulates in esophageal squamous cell carcinoma (ESCC) in advanced stage of the disease and is negatively associated with the survival of ESCC patients. The PD1 tumor-associated macrophages (PD1 TAMs) displayed surface pattern and function akin to M2: a substantial enhancement in CD206 and IL-10 expression; a specific reduction in HLA-DR, CD64, and IL-12 expression; and a significant increase in the ability to inhibit CD8 T-cell proliferation. Triggering of PD1 signal is effective in increasing PD1 TAM function. Moreover, exosomal HMGB1 obtained from tumors are efficient in triggering differentiation of monocytes into PD1 TAMs, which display phenotypic and functional properties of M2. Overall, our work is the first finding to confirm that exosomal HMGB1 obtained from ESCC can successfully trigger clonal expansion of PD1 TAM. Further, as the macrophages exhibit an M2-like surface profile and function, thereby creating conditions for development of ESCC. Thus, effective methods of treatment include combining immunotherapy with targeting PD1 TAMs and tumor-derived exosomal HMGB1 to resuscitate immune function in individuals suffering from ESCC.