Abstract 3180: Blockade of PD-L1 interaction with CD80 in trans augments anti-tumor immunity by increasing NOS2 in tumor-associated macrophages
Authors: Zhang Yuankun , Song Qingxiao , Lee Michael , Tang Haidong , Cassady Kaniel , Fu Yang-Xin , Schones Dustin E. , Riggs Arthur , Feng Ru , Zeng Defu 
Published: July 2021

Programmed death ligand 1(PD-L1) has two receptors: programmed death receptor 1 (PD-1) and CD80. Both PD-L1 and CD80 are expressed by activated T-cells, antigen presenting cells (APCs) and tumor cells. Although the role of PD-L1/PD-1 interaction in regulation of tumor immunity has been well characterized, role of PD-L1/CD80 interaction remains largely unknown. The interaction mode of PD-L1 with CD80 is also controversial. Our previous studies showed that in murine model of acute graft versus host disease, PD-L1 interact with CD80 on different cells (Deng et al: J. Immunol. 2015); but a recent report showed that PD-L1 interacts with CD80 in cis on the same cell (Sugiura et al: Science 2019). In the current studies, we tested the role of PD-L1/CD80 interaction in trans in regulation of tumor immunity. WT, PD-L1-/-, and CD80-/- C57BL/6 mice were inoculated with WT or PD-L1-/- MC38 tumor cells and intraperitoneally injected with 200μg anti-PD-L1(43H12) that specifically block PD-L1/CD80 interactions or control IgG, starting on D7 after tumor inoculation, every 3 days, total of 5 times. Tumor volume was monitored every 3 days for up to D20. Tumor and tumor draining lymph nodes were harvested on D14 or D15 after tumor inoculation for mechanism studies. We observed that administration of 43H12 resulted in inhibition of tumor growth in WT MC38→WT Rec model; as well as in models of WT MC38→PD-L1-/- Rec (no PD-L1 on APCs or T cells), WT MC38→CD80-/- Rec (no CD80 on APCs or T cells), and PD-L1-/-MC38→CD80-/- Rec (no PD-L1 on tumor cells and no CD80 on APCs or T cells, truly PD-L1 interaction with CD80 in trans). These results indicate that blockade of PD-L1 interaction with CD80 in trans inhibits tumor growth. Furthermore, we found that blockade of PD-L1/CD80 interaction by 43H12 mAb increased percentage of CD8+ effector memory T (Tem) that produce IFN-γ and tumor-associated macrophages (TAMs) that express NOS2. Administration of anti-IFN-γ eliminated increase of NOS2 and anti-tumor effect, and administration of NOS2 inhibitor (1400W) also eliminated the anti-tumor effect mediated by injection of 43H12 mAb. Therefore, PD-L1 interaction with CD80 in trans regulate tumor immunity; and blockade of this interaction augments anti-tumor immunity via augmenting CD8+ Tem expansion and their production of IFN-γ, and subsequently augmenting tumoricidal NOS2 expressed in TAMs.

Citation Format: Yuankun Zhang, Qingxiao Song, Michael Lee, Haidong Tang, Kaniel Cassady, Yang-Xin Fu, Dustin E. Schones, Arthur Riggs, Ru Feng, Defu Zeng. Blockade of PD-L1 interaction with CD80 in trans augments anti-tumor immunity by increasing NOS2 in tumor-associated macrophages [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 3180.