PRTN3 suppresses cytotoxic immune-cell activation and antitumoral immunity through proteolytic cleavage of CXCL9 in KRAS mutant lung adenocarcinoma

The intratumoral activity of chemokine system has important roles in cancer immunotherapy strategies.One of the mechanisms of immune checkpoint blocking (ICB)resistance may be the dysfunction of chemokine signaling. Here, we first report that KRAS mutation in LUAD cells up-regulates the expression of protease 3 (PRTN3), that inhibits cytotoxic immune cell activation in the tumor microenvironment by inhibiting the CXCL9/CXCR3 axis, providing an unconventional mechanism for tumor immune escape. Further mechanism studies demonstrated that PRTN3 was up-regulated by c-Myc transcription and secreted into the tumor microenvironment, where CXCL9 was inactivated by proteolysis, and finally result in inhibiting the activation of natural killer (NK) and CD8+ T cells. Meanwhile, samples from LUAD patients with high PRTN3 expression showed low CXCL9 activity. Furthermore, application of a hydrolysis-resistant CXCL9 protein (H-R CXCL9) effectively improves the immunomodulate effect in LUAD patient organoids. Importantly, PRTN3 knockdown increased the susceptibility of KRAS mutant cells to Anti-pd-1 therapy. Thus, we have identified a previously unknown tumor immune-suppressive mechanism and provided an immunotherapeutic target to improve the effectiveness of ICB therapy in KRAS mutant LUAD.