1201 Melanoma cell-intrinsic TNFAIP3 promotes tumor progression and immune escape by activating STAT3

Ubiquitin-editing enzymeTNFAIP3 is well known for its anti-inflammatory activity and has been greatly implicated in anti-tumor immunity in immune cells. However, little is known about tumor cell-intrinsic TNFAIP3 effects. In the present study, we demonstrate that melanoma cell-intrinsic TNFAIP3 promotes tumorigenesis. We first found that TNFAIP3 was significantly up-regulated in both melanoma tissues and cell lines, compared to melanocytic nevus and normal human melanocytes respectively. Then, the knockdown of TNFAIP3 significantly attenuated the proliferation, invasion and migration of melanoma cells in vitro and suppressed transplanted tumor growth and metastasis in vivo. Subsequent mechanistic study revealed that the oncogenic role of TNFAIP3 was dependent on its positive regulatory effect on STAT3 signaling. More importantly, we found that TNFAIP3 promoted immune checkpoint PD-L1 expression in melanoma cells through activating STAT3. TNFAIP3 deficiency in melanoma potentiated cytotoxicity of infiltrated CD8+ T cells in tumor microenvironment and enhanced the anti-tumor immunity, thus leading to melanoma regression in vivo.In conclusion, our results demonstrate that melanoma cell-intrinsic TNFAIP3 promotes tumor progression and immune escape by activating STAT3.