Abstract 1835: A synergistic antitumor effect of PLAG with aPD-1 by modulating the adenosine signaling pathway in ICI low-sensitivity CRC model

Abstract Background: Immune checkpoint inhibitors (ICIs) have been proven to be very effective and have fewer side effects than conventional anticancer drugs by responding specifically to tumors. However, tumors developed resistance through various tumor-friendly factors, gradually weakening the effects of ICI. These factors suppress the activation of cytotoxic T-lymphocytes (CTLs), thereby inhibiting the ICI efficacy on tumors. Therefore, it is very important to develop a combination therapy that induces the anticancer efficacy of ICI by suppressing resistance factors produced by tumors. Our previous results demonstrated that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) effectively controls the tumor-friendly factors (neutrophils infiltration, adenosine, etc.) while increasing CTL infiltration to suppress tumor progression. We suggest that PLAG is one of the effective alternatives to enhance the antitumor efficacy of ICI. Method: CT26 colorectal carcinoma (CRC) cell was inoculated into the syngeneic Balb/c mice SC and maintained for 4 days. PLAG (25/50/100 mpk) was daily administered orally for 3 weeks w/wo 5 mpk aPD-1 (RMP1-14) via IP once/week. AZD4635 was daily administered orally at 30 mpk, and anti-CD73 by IP at 10 mpk twice/week. Tumor growth was measured in 3-day intervals. Result: aPD-1 treatment inhibited tumor growth by 39%, whereas the aPD-1/PLAG treatment reduced tumor growth by 85% in the CT26 ICI low-sensitivity CRC model. Tumor weight was reduced by 17.5% in aPD-1, whereas aPD-1/PLAG treatment decreased by 68%. PLAG treatments (PLAG only group: 4 out of 6, PLAG/aPD-1 combination group: 5 out of 6) significantly improved the survival rate of tumor-bearing mice compared to control or aPD-1 group (2 out of 6) (p<0.0019). PLAG significantly increased tumor infiltration of CTLs while effectively controlling infiltration of tumor-friendly active neutrophils, as well as induced M1-type macrophage polarization (p<0.05). Importantly, PLAG suppressed the production of adenosine and ATP, which is involved in tumor progression. PLAG showed superior antitumor efficacy compared to current ICI combination therapies targeting the adenosine signaling pathway (AZD4635: A2AR antagonist, anti-CD73: inhibition of extracellular adenosine production). PLAG improved survival rate (AZD4635: 3 out of 6, PLAG: 4 out of 6; p<0.0394) and reduced the tumor size by 14% compared with AZD4635/aPD-1. Conclusion: Our findings show that PLAG inhibits tumor growth by suppressing massive adenosine production, which may increase the antitumor efficacy of aPD-1 through improved CTLs infiltration. We propose that PLAG could be a novel therapeutic strategy for patients with ICI-resistant tumors. Citation Format: Jae Sam Lee, Guen Tae Kim, Eun Young Kim, Su-Hyun Shin, Hyowon Lee, Se Hee Lee, Ji Won Choi, Dong Sung Kim, Ki-Young Sohn, Jae Wha Kim. A synergistic antitumor effect of PLAG with aPD-1 by modulating the adenosine signaling pathway in ICI low-sensitivity CRC model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1835.