Peptide Blocking of PD-1/PD-L1 Interaction for Cancer Immunotherapy.

Chunlin Li,Chen Ding,Xueyuan Cui,Kefeng Pu,Jundong Zhou,Yaqing Jin,Nengpan Zhang,Yimin Zhu

doi:10.1158/2326-6066.cir-17-0035

Abstract

Immunotherapy has become a promising alternative therapeutic approach for cancer patients. Interruption of immune checkpoints, such as CTLA-4 and PD-1, has been verified to be a successful means for cancer therapy in clinical trials. mAb targeting PD-L1 has been approved to treat urothelial carcinoma, non-small cell lung cancer, or Merkel cell carcinoma by the FDA. However, the high cost of the antibody can limit its application. In our study, targeting PD-L1 peptide (TPP-1), which specifically binds to PD-L1 with high affinity, was identified through bacterial surface display methods. Using a T-cell activation assay and mixed lymphocyte reaction, TPP-1 was verified to interfere with the interaction of PD-1/PD-L1. To examine the inhibitory effect of TPP-1 on tumor growth in vivo, a xenograft mouse model using H460 cells was established. The growth rate of tumor masses in TPP-1 or PD-L1 antibody-treated mice was 56% or 71% lower than that in control peptide-treated mice, respectively, indicating that TPP-1 inhibits, or at least retards, tumor growth. IHC of the tumors showed that IFNγ and granzyme B expression increased in the TPP-1 or PD-L1 antibody-treated groups, indicating that TPP-1 attenuates the inhibitory effect of PD-L1 on T cells and that T cells may get reactivated. On the basis of our data, TPP-1 peptide could work as an alternative to antibodies for tumor immunotherapy. Cancer Immunol Res; 6(2); 178-88. ©2017 AACR.

Highlights

IntroductionT cells need to receive antigenindependent costimulatory signals through the corresponding receptors
To become fully activated, T cells need to receive antigenindependent costimulatory signals through the corresponding receptors
Cancer immunotherapy with anti–CTLA-4 has achieved modest success in clinical practice in the past several years, data collected from both animal experiments and clinical trials indicate a potential risk of autoimmunity or other severe adverse events related to anti–CTLA-4 administration [3, 4]

Summary

Introduction

T cells need to receive antigenindependent costimulatory signals through the corresponding receptors. Coinhibitory receptors are expressed on T cells to regulate their activation, tolerance, and immunopathology, thereby balancing the immune system [1]. 2) is a critical inhibitory receptor expressed on cytotoxic T lymphocyte cells and acts as an important brake in the regulation of cell-cycle progression. Cancer immunotherapy with anti–CTLA-4 has achieved modest success in clinical practice in the past several years, data collected from both animal experiments and clinical trials indicate a potential risk of autoimmunity or other severe adverse events related to anti–CTLA-4 administration [3, 4]. Programmed cell death 1 (PD-1, CD279) and programmed cell death ligand 1 (PD-L1, Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/)

Methods

Results

Conclusion