Hedgehog-induced PD-L1 on tumor-associated macrophages is critical for suppression of tumor-infiltrating CD8+ T cell function.

Amy J Petty,Robert A Baiocchi,Zihai Li,Rosa Lapalombella,Yiping Yang,Xiaopei Huang,Don M Benson,Rui Dai

doi:10.1172/jci.insight.146707

Abstract

The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ–dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1-knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8+ T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8+ T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.

Highlights

The programmed death-1/programmed death ligand 1 (PD-1/PD ligand 1 (PD-L1)) axis of interaction is one of the most important immunosuppressive mechanisms within the tumor microenvironment (TME), and targeting this mechanism has led to exciting therapeutic advances in clinical oncology [1,2,3,4,5,6]
CD8+ T cells in the tumors treated with anti– PD-L1 antibodies demonstrated a marked increase in effector function measured by IFN-γ and granzyme B (GzmB) production
We provided proof that tumor-associated macrophages (TAMs)-derived PD-L1 expression is critical for suppressing intratumor CD8+ T cell function in vivo

Summary

Introduction

The programmed death-1/programmed death ligand 1 (PD-1/PD-L1) axis of interaction is one of the most important immunosuppressive mechanisms within the tumor microenvironment (TME), and targeting this mechanism has led to exciting therapeutic advances in clinical oncology [1,2,3,4,5,6]. While PD-1 was mainly found on the intratumoral lymphocyte population, PD-L1 expression has been observed on a diverse group of cells, including tumor cells, myeloid cells, lymphocytes, and stromal cells [7]. It has been difficult to query the precise role of PD-L1 on each of the cell populations within the TME due to the lack of a conditional ready Pdl1fl/fl mouse model that allows for lineage-specific deletion of Pdl. After breeding to LysM-cre mice expressing Cre recombinase in myeloid cells [16], these mice showed a complete deletion of Pdl in myeloid lineage cells. This allowed us to directly study the role of TAM-derived PD-L1 in subverting adaptive immune responses within the TME

Methods

Results

Conclusion