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

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.

Type I interferon-mediated tumor immunity and its role in immunotherapy

“…In addition, a study found that autocrine IFN-α/β from the TME upregulates TRAIL expression on activated T cells, which elicits MDSC apoptosis through the TRAIL–DR5 pathway. Furthermore, they found that using neutralizing IFNAR1 abolishes the type I IFN-induced MDSC apoptosis [ 70 ].…”

MDSC in Mice and Men: Mechanisms of Immunosuppression in Cancer

“…In addition to the humanized mice, patient-derived organoids could be a creative model that accounts for longer time-courses and more diverse cell-cell interactions [160,161]. However, in vitro organoids often aim to represent the TME only.…”

Hepatic RACK1 deficiency protects against fulminant hepatitis through myeloid-derived suppressor cells

“…Since anti-Gr1 antibody treatment could also deplete neutrophils 33 , a more specific antibody should be used to target MDSCs. Activation of endoplasmic reticulum stress is a common feature of MDSCs in both mice and humans, inducing the upregulation of DR5, a TRAIL receptor 34 , 35 . It has been reported that targeting DR5 could specifically induce MDSC apoptosis 35 , 36 .…”

“…Activation of endoplasmic reticulum stress is a common feature of MDSCs in both mice and humans, inducing the upregulation of DR5, a TRAIL receptor 34 , 35 . It has been reported that targeting DR5 could specifically induce MDSC apoptosis 35 , 36 . Elevated DR5 expression of Ly6G hi Ly6C lo , but not Ly6G lo Ly6C hi , myeloid cells in RACK1-deficient livers was observed by flow cytometry compared to their counterparts in RACK1-sufficient livers (Figure 3 E).…”