Next-generation immunotherapy for solid tumors: combination immunotherapy with crosstalk blockade of TGFβ and PD-1/PD-L1

Abstract

Introduction: In solid tumor immunotherapy, less than 20% of patients respond to anti-programmed cell death 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) agents. The role of transforming growth factor β (TGFβ) in diverse immunity is well-established; however, systemic blockade of TGFβ is associated with toxicity. Accumulating evidence suggests the role of crosstalk between TGFβ and PD-1/PD-L1 pathways.

Areas covered: We focus on TGFβ and PD-1/PD-L1 signaling pathway crosstalk and the determinant role of TGFβ in the resistance of immune checkpoint blockade. We provide the rationale for combination anti-TGFβ and anti-PD-1/PD-L1 therapies for solid tumors and discuss the current status of dual blockade therapy in preclinical and clinical studies.

Expert opinion: The heterogeneity of tumor microenvironment across solid tumors complicates patient selection, treatment regimens, and response and toxicity assessment for investigation of dual blockade agents. However, clinical knowledge from single-agent studies provides infrastructure to translate dual blockade therapies. Dual TGFβ and PD-1/PD-L1 blockade results in enhanced T-cell infiltration into tumors, a primary requisite for successful immunotherapy. A bifunctional fusion protein specifically targets TGFβ in the tumor microenvironment, avoiding systemic toxicity, and prevents interaction of PD-1+ cytotoxic cells with PD-L1+ tumor cells.

Keywords: Crosstalk; PD-1; PD-L1; TGFβ; dual blockade therapy.

Figure 1.. Schematic representation of TGFβ and PD-1/PD-L1 targeting monotherapies in clinical trials.

(A) Anti-TGFβ–signaling drugs are characterized into three approaches: antisense oligonucleotides blocking TGFβ mRNA translation, monoclonal antibodies neutralizing TGFβ molecules, and receptor kinase inhibitors blocking intracellular signals. (B) Anti–PD-1/PD-L1 drugs are classified into two levels: ligand level disrupting PD-L1–PD-1 interaction, and intracellular level suppressing downstream signal transduction of PD-1. Abbreviations: Transforming growth factor β (TGFβ); programmed cell death 1(PD-1); programmed cell death 1 ligand 1 (PD-L1)

Figure 2.. Interplay of TGFβ and PD-1/PD-L1 signaling upon TCR/CD28 activation in T-cell.

(1) Upon antigen engagement, TCR/CD3 chain is phosphorylated, as well as CD8 and CD28. Lck and Zap70 are recruited to ITAM site and activated, resulting in the phosphorylation of downstream signaling, mainly including PKCθ, PI3K and Ras. Finally, antigen presentation leads to the nuclear translocation of NFATc1 and NF-κB, thereby activating T-cell proliferation and functionality as well as Pdc1 transcription. (2) PD-1/PD-L1 ligation directly suppresses TCR signaling by the attenuation of Lck, PI3K/Akt and Ras/Erk at multiple stages, resulting in inhibition of anti-tumor cytotoxicity, accelerating T-cell exhaustion and apoptosis. Moreover, PD-1 signaling polarizes naïve T-cell differentiation and promotes Treg proliferation, leading to an excessive production of TGFβ. (3) PD-1 signaling enhances the expression of itself by countering the process of FoxO1 phosphorylation via PI3k/Akt targeting, thus preventing FoxO1 sequestration and enabling Pdcd1 transactivation. (4) TGFβ signaling initiates the transcription of Pdcd1 by canonical pathway (SMAD2/3 & SMAD4) and contributes to PD-1 expression via non-canonical pathway (TRAF6-TAK1). All the above shows a sophisticated pattern illustrating that TGFβ and PD-1/PD-L1 signaling promote each other in a positive feedback manner to impair the anti-tumor CTL response. Abbreviations: Transforming growth factor β (TGFβ); programmed cell death 1(PD-1); programmed cell death 1 ligand 1 (PD-L1); major histocompatibility complex (MHC); T-cell receptors (TCR)

Figure 3.. An overview of dual blockade therapies in current clinical trials.

Combination therapies of TGFβ and PD-1/PD-L1 are under investigation in clinical trials including: TGFβ antibody + PD-1 antibody, TGFβ antibody + PD-L1 antibody, TGFβRI kinase inhibitor + PD-1 antibody, TGFβRI kinase inhibitor + PD-L1 antibody. Abbreviations: Transforming growth factor β (TGFβ); TGFβ receptor (TGFβR); programmed cell death 1(PD-1); programmed cell death 1 ligand 1 (PD-L1)

Figure 4.. Classification of dual anti-PD-1/PD-L1 and anti-TGFβ blockade strategies in both pre-clinal and clinical evaluations.

(1) combination of anti–PD-L1 mAb (6E11, MIH5, 10F.9G2) and anti-TGFβ mAb (1D11). (2) combination of anti–PD-1 mAb (RMP1–14, BE0146, Spartalizumab, Cemiplimab) and anti-TGFβ mAb (1D11, SAR439459, NIS793). (3) Fusion antibody: Anti-PDL1 mAb linked to two extracellular domains of TGFβR II molecules (M7824, SHR-1701). (4) combination of anti–PD-L1 mAb (Durvalumab,178G7, LY3300054) and TGFβRI inhibitor (Vactosertib, LY3200882). (5) combination of anti–PD-1 mAb (Pembrolizumab, RMP1–14) and TGFβR inhibitor (Galunisertib, SRK-181, LY3200882). Abbreviations: Transforming growth factor β (TGFβ); TGFβ receptor (TGFβR); programmed cell death 1(PD-1); programmed cell death 1 ligand 1 (PD-L1); monoclonal antibody (mAb)