B16 melanoma control by anti-PD-L1 requires CD8+ T cells and NK cells: application of anti-PD-L1 Abs and Trp2 peptide vaccines

ABSTRACT

Anti-programmed death ligand 1 (PD-L1) therapy has been beneficial in treating patients with certain cancers. Here, we tested whether anti-PD-L1 therapy is effective for controlling different types of tumors using animal models of TC-1, MC38 and B16. We found that, despite PD-L1 expression, anti-PD-L1 therapy showed little and some antitumor activity in the TC-1 and MC38 models. However, anti-PD-L1 therapy exhibited a more dramatic antitumor effect in the B16 model. This difference in antitumor responses was likely associated with the CD8 + T cell infiltration status of tumor tissues. In the B16 model, CD8 + T cells and to a lesser degree NK cells were found to be responsible for the antitumor response of anti-PD-L1 therapy, as determined by immune cell subset depletion. In particular, CD8 + T cells from B16-bearing mice produced an IFN-γ in response to B16 cells and citrate phosphate buffer-treated B16 cell peptide elutes but not to an immunodominant class I epitope, Trp2_180-188, suggesting that CD8 + T cells that recognize neoantigens were induced in B16 tumor-bearing mice and then reactivated by anti-PD-L1 for tumor control. When B16 tumor-bearing mice were treated with anti-PD-L1 in combination with Trp2_180-188 peptide vaccines, they displayed significantly more tumor control than either single therapy. Taken together, these studies show that B16 melanomas are more effectively controlled through reactivation of tumor-infiltrating lymphocytes by anti-PD-L1 therapy. Moreover, combined therapy using anti-PD-L1 and Trp2 peptide vaccines is more beneficial for controlling B16 melanomas through reactivation of neoantigen-specific CD8 + T cells and induction of Trp2-specific CD8 + T cells.

KEYWORDS:

• Anti-PD-L1
• cancer immunotherapy
• melanoma
• peptide vaccine

Supplementary Material

Supplemental data for this article can be accessed on the publisher’s website.

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (NRF-2018R1D1A1B07040656). Dr. Joo Hee Chung at the Korea Basic Science Institute (SEOUL) is thanked for taking data in HPLC.