Reprogramming immunosuppressive myeloid cells by activated T cells promotes the response to anti-PD-1 therapy in colorectal cancer

Jing Chen,Limin Zheng,Yi-Tuo Xu,Xiao-Jun Wu,Wen-Chao Wu,Yan-Yan Yang,Jing Xu,Hai-Tian Chen,Hong-Wei Sun,Li-Lian Jin,Xing-Juan Yu

doi:10.1038/s41392-020-00377-3

Abstract

Overcoming local immunosuppression is critical for immunotherapy to produce robust anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) are key regulators of immunosuppressive networks and promote tumor progression. However, it remains unclear whether and how tumor-infiltrating MDSCs are shaped in response to anti-PD-1 treatment and what their impact on therapeutic efficacy is in colorectal cancer (CRC). In this study, the levels of infiltrating MDSCs were significantly higher in the non-responding organoids and were selectively reduced in the responding group, with MDSCs showing increased apoptosis and attenuated functional activity after anti-PD-1 treatment. A negative correlation between T-cell activation and MDSC function was also observed in fresh human CRC tissues. Mechanistic studies revealed that autocrine IFN-α/β upregulated TRAIL expression on activated T cells to elicit MDSC apoptosis via the TRAIL–DR5 interaction and acted synergistically with TNF-α to inhibit MDSC function of suppressing the T-cell response through the JNK-NMDAR-ARG-1 pathway. Moreover, blockade of IFN-α/β and TNF-α abolished the therapeutic efficacy of anti-PD-1 treatment by preserving the frequency and suppressive activity of infiltrating MDSCs in a CRC mouse model. This result suggested that reprogramming MDSCs by IFN-α/β and TNF-α from activated T cells was necessary for successful anti-PD-1 treatment and might serve as a novel strategy to improve the response and efficacy of anticancer therapy.

Highlights

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that universally regulate the immune response under many pathological conditions.[1,2,3] These cells often accumulate in tumors, playing a crucial role in the immunosuppressive tumor microenvironment (TME)
IFN-α/β and tumor necris factor-α (TNF-α) secreted by activated T cells cooperate to inhibit MDSC function induced MDSCs were cocultured with different ratios of T cells that we investigated the mechanisms by which soluble subhad been activated by CD3 and CD28 antibodies, and recombi- stances from activated T cells regulate MDSC function (Fig. 2c)
The Activated T cells suppress MDSC function through the JNKNMDAR-ARG-1 pathway To further explore the signaling mechanisms by which activated T-cell supernatant (ASN) modulates MDSC function, we investigated the roles of nuclear factor-κB (NF-κB), signal transducer and activator of transcription 1 (STAT1), STAT3, c-Jun N-terminal kinase (JNK), mammalian target of rapamycin, AKT, and extracellular signal-regulated kinase (ERK), all of which are members of the downstream signaling pathways of type I IFNs and TNF-α

Summary

1234567890();,: INTRODUCTION

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that universally regulate the immune response under many pathological conditions.[1,2,3] These cells often accumulate in tumors, playing a crucial role in the immunosuppressive tumor microenvironment (TME). Colorectal cancer (CRC) progression is often associated with chronic inflammation[16,17] and the infiltration of cytotoxic and memory T cells in CRC tissues could be a useful marker to predict good prognosis.[18,19,20] CRC with mutations in the mismatch repair pathway, which are associated with increased TIL infiltration, could be more responsive to ICB, but the general benefits remain limited.[21,22,23,24] Recently, we observed that several human tumor tissues, including CRC, are enriched with MDSCs. The selective targeting of tumor-infiltrating MDSCs could improve the efficacy of anti-PD-L1 treatment in a mouse model.[4] it remains unclear whether and how the remodeled TME after ICB could regulate the accumulation and function of MDSCs in CRC tissues. Transwell assays showed ligand (TRAIL) expression on activated T cells to elicit MDSC apoptosis via the TRAIL–DR5 interaction and act synergistically with tumor necris factor-α (TNF-α) to inhibit the suppressive that the cytotoxic effect of T cells on MDSCs largely relied on cell–cell contact (Fig. 2b). These data indicated that intercellular contact is required to induce MDSC apoptosis when

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS