Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages.

Oral squamous cell carcinoma (OSCC) is the most common solid tumor in the oral cavity. Development and progression of OSCC is associated with the elevated presence of inhibitory M2 type tumor-associated macrophages (TAMs). However, the underlying mechanism leading to the enrichment of M2 TAMs and the pathway through which TAMs foster tumor progression are still unclear. In this study, we harvested TAMs and tumor cells from primary OSCC resections of stage II and stage III patients. We showed that compared to peritumoral macrophages, TAMs presented upregulated expression of PD-L1 and elevated capacity in inducing T cell apoptosis. The level of PD-L1 expression directly correlated with the level of T cell apoptosis. Interestingly, peripheral blood monocytes with low initial PD-L1 level had upregulated PD-L1 expression and acquired the ability to induce T cell apoptosis, after incubation with primary tumor cells from OSCC patients. The PD-L1 expression by monocytes depended on interleukin 10 (IL-10), since blockade of IL-10 in the tumor-monocyte coculture abrogated PD-L1 upregulation. IL-10 mRNA expression in tumor cells and monocytes also preceded PD-L1 mRNA expression in monocytes. Furthermore, the IL-10 concentration in the tumor microenvironment directly correlated with the PD-L1 level on TAMs. Together, these results suggest that OSCC could directly suppress antitumor T cell immunity through conditioning TAMs.

Jiang C ，Yuan F ，Wang J ，Wu L ... -  《-》

Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment.

Hirai M ，Kitahara H ，Kobayashi Y ，Kato K ，Bou-Gharios G ，Nakamura H ，Kawashiri S ... -  《-》

Tumor cell-released autophagosomes (TRAPs) promote immunosuppression through induction of M2-like macrophages with increased expression of PD-L1.

Wen ZF ，Liu H ，Gao R ，Zhou M ，Ma J ，Zhang Y ，Zhao J ，Chen Y ，Zhang T ，Huang F ，Pan N ，Zhang J ，Fox BA ，Hu HM ，Wang LX ... -  《Journal for ImmunoTherapy of Cancer》

CD163(+)CD204(+) tumor-associated macrophages contribute to T cell regulation via interleukin-10 and PD-L1 production in oral squamous cell carcinoma.

Kubota K ，Moriyama M ，Furukawa S ，Rafiul HASM ，Maruse Y ，Jinno T ，Tanaka A ，Ohta M ，Ishiguro N ，Yamauchi M ，Sakamoto M ，Maehara T ，Hayashida JN ，Kawano S ，Kiyoshima T ，Nakamura S ... -  《Scientific Reports》

IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma.

We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC). The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies. We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3 p axis. Monocytes and TAMs showed significantly increased miR-25-3 p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3 p-modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1-induced immunosuppression in an orthotopic tumor transplantation model. Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

Zhang W ，Liu Y ，Yan Z ，Yang H ，Sun W ，Yao Y ，Chen Y ，Jiang R ... -  《Journal for ImmunoTherapy of Cancer》