Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy

Abstract

Programmed death receptor ligand 1 (PD-L1, also called B7-H1) is a recently described B7 family member. In contrast to B7-1 and B7-2, PD-L1 does not interact with either CD28 or CTLA-4. To date, one specific receptor has been identified that can be ligated by PD-L1. This receptor, programmed death receptor 1 (PD-1), has been shown to negatively regulate T-cell receptor (TCR) signaling. Upon ligating its receptor, PD-L1 has been reported to decrease TCR-mediated proliferation and cytokine production. PD-1 gene-deficient mice developed autoimmune diseases, which early led to the hypothesis of PD-L1 regulating peripheral tolerance. In contrast to normal tissues, which show minimal surface expression of PD-L1 protein, PD-L1 expression was found to be abundant on many murine and human cancers and could be further up-regulated upon IFN-gamma stimulation. Thus, PD-L1 might play an important role in tumor immune evasion. This review discusses the currently available data concerning negative T-cell regulation via PD-1, the blockade of PD-L1/PD-1 interactions, and the implications for adoptive T-cell therapies.

Fig. 1

Schematic description of the requirements for an CD8⁺ T-cell–mediated antitumor immune response. Naïve tumor-specific CD8⁺ T cells can be activated directly from tumor cells or indirectly from APCs presenting TAA. In a second step, differentiation toward a type I phenotype is optimal. This step is favored by IL-12 and IFN-γ and suppressed by IL-4 or IL-13. Furthermore, sufficient expansion of tumor-specific T cells is important and may require IL-2. Activation-induced nonresponsiveness (AINR), anergy induction, and T-cell deletion may interfere with sufficient expansion and in vivo survival. Tumor penetration is influenced by chemokines and adhesion molecules. Furthermore, the interaction between tumor-specific T cells and the tumor cell is improved by high MHC expression, high antigen densitiy on the tumor, and B7 expression of the tumor. Immune escape might be mediated via TGF-β, MHC loss, or engagement of Fas, PD-1, or CTLA-4 on the T cell. Finally, long-term responses require the development of a memory immune response.

Fig. 2

The growing number of B7 superfamily members shaping TCR signaling. CD28 and CTLA-4 have MYPPPY motifs that are essential to bind B7-1 (CD80) and B7-2 (CD86). B7-1 and B7-2 provide important costimulatory signals via an interaction with the constitutively expressed CD28 and provide a negative signal via CTLA-4 (CD152), which is induced upon T-cell activation. ICOS (H4) does not show any binding to B7 and seems to mediate costimulatory effects on recently activated and effector T cells binding to its ligand, ICOS-L (B7 h, B7-H2). B7-H3 is constitutively expressed on IFN-γ–treated DCs and binds to an unidentified receptor on activated, but not on resting, T cells. B7-H3 costimulates proliferation of CD4⁺ and CD8⁺ T cells. PD-L1 (B7-H1) negatively regulates proliferation and cytokine production of T and B cells that express PD-1 upon activation. A secondary receptor mediating costimulatory signals from PD-L1 has been postulated, but not yet identified. This receptor possibly interacts preferentially with PD-L2 (B7-DC). B7x (B7-H4) has been reported to interact with BTLA, which is expressed on activated T and B cells, inhibiting lymphocyte activation. In contrast to the APC shown here, most tumor cells lack B-7 costimulatory molecules and express strongly PD-L1, either constitutively or upon IFN-γ. This expression pattern might shift the costimulatory balance of the TCR signal toward inhibition of tumor-specific T cells when interacting with the tumor cell.