Suppressive Effect Of Plag On Tumor Progression And Its Synergistic Therapeutic Effect With Ici Therapy Through Adenosine Clearance.

Abstract Background: There are limited side effects with ICI therapy such as not responding or reduced therapeutic effect caused by its tolerance. In particular, adenosine-induced tumor progression and drug adaptability are the obstacles in use of ICI therapy. Removing adenosine around the tumor is a prerequisite factor of improving the effect of ICI therapy along with suppression of tumor progression. Methods: To investigate the anti-tumor effect of PLAG with the PD-1 antibody (aPD-1), the syngeneic model was used (n=6/group). LLC-1 lung carcinoma cells were implanted into the C57BL/6 mice via subcutaneous. PLAG was daily administrated for 4 weeks with or without 5 mpk of aPD-1 (RMP1-14). it was delivered via IP injection biweekly. The adenosine levels and infiltrated immune cell populations in the tumor and blood were analyzed weekly until the sacrifice day. Results: The tumor size decreased by 23%/65%/81% in a dose-dependently compared to the positive control. Especially, the tumor completely disappeared in 1 animal in treated with aPD-1 and 50 mpk of PLAG, and the 2 animals in treated with 100 mpk. The adenosine levels of blood and tumor burden in the PLAG-treated group decreased by more than 50% compared to the positive control group. It was also confirmed that the adenosine level was about 25% lower in the PLAG-treated group compared to the aPD-1 alone. We found that the expression of A2B receptor in the tumor was significantly reduced in PLAG-treated group. Interestingly, the tumor growth inhibitory effect of PLAG was about 23% better than MRS1754, an A2B receptor antagonist. MRS1754-treated group showed significantly high adenosine level in the blood and tumor, whereas, in the PLAG-treated group, similar adenosine level in blood was continuously maintained as the negative control and its level in the tumor was decreased compared to the positive control. Increasing cancer cell growth and adenosine secretion were shown at 8 h post-treatment of adenosine. PLAG co-treatment decreased the adenosine level by half rapidly and then reduced continuously. In particular, degradation of the A2B receptor was observed after 4 h in PLAG-treated cells. Also intracellular ROS generated during the trafficking of the receptor was elevated within a short period by PLAG and then rapidly decreased at the same time as the signal protein change. PLAG may induce intracellular ROS regulation and A2B receptor degradation through overexpression of αARR. The effect of PLAG disappeared when αARR was knock-down. Conclusion: Extracellular adenosine level of tumor in ICI therapy could be the critical factor to be a successful anticancer treatment. To attenuate adenosine levels, a number of targeted therapies are being developed. Unlike these targeted therapeutics, PLAG fundamentally blocks cancer growth by adenosine clearance. Therefore, PLAG has its own anti-cancer effect and can maximize the effect of ICI therapy. Citation Format: Guen Tae Kim, Sun Young Yoon, Kaapjoo Park, Heesoo Kim, Ki-Young Sohn, Jae Wha Kim. Suppressive effect of PLAG on tumor progression and its synergistic therapeutic effect with ICI therapy through adenosine clearance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1447.