On October 11, 2022, the team of Cai Zhijian of Zhejiang University published a research paper online in Cellular & Molecular Immunology, which showed that tumor extracellular vesicles regulate anti-PD-L1 treatment resistance by inducing anti-PD-L1.

This article is original from Translational Medicine Network. Please indicate the source for reprinting

Author: Jevin

Introduction: PD-L1+Tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and may cause drug resistance against PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1 treatment resistance is not known.

On October 11, 2022, Zhejiang University Cai Zhijian's team published a research paper online in "Cellular Molecular Immunology" . This study showed that tumor extracellular vesicles regulate anti-PD-L1 treatment resistance by inducing anti-PD-L1. study found that PD-L1+ TEVs largely tricked αPD-L1, and TEVs-bound αPD-L1 was removed faster by macrophages , resulting in insufficient blockade of tumor PD-L1 and subsequent resistance to αPD-L1 treatment. inhibits endogenous TEVs production by Rab27a or Coro1a knockdown reverses αPD-L1 treatment resistance.

https://www.nature.com/articles/s41423-022-00926-6

Research background

01

extracellular vesicles (EVs) are mainly divided into two categories: exosomes and exosomes. Exosomes are vesicles that sprout directly outward through the plasma membrane. Exosomes are produced by endosomal pathways. EV contains a large amount of protein , nucleic acids, lipids and metabolites from its parent cells and is critical for communication between cells. It is reported that PD-L1 occurs on tumor-derived EV (TEV), and TEV PD-L1 plays a central role in inducing immune escape. PD-L1 on melanoma-derived EV inhibits CD8 T cells activation and promotes tumor growth. TEV PD-L1 induces systemic immunosuppression and appears to be resistant to αPD-L1 treatment. TEV PD-L1 is associated with immunotherapy resistance. These findings suggest that TEV PD-L1 may be the cause of resistance to αPD-L1 treatment. However, the specific mechanism of resistance mediated by TEV PD-L1 is not clear. Two secreted PD-L1 splicing variants of lack transmembrane domains and have been shown to act as "bait" for αPD-L1, resulting in αPD-L1 therapeutic resistance. Likewise, it is not clear whether TEV PD-L1 may also induce αPD-L1 resulting in αPD-L1 depletion and subsequent therapeutic resistance, in addition to inhibitory signaling by binding PD-1 on T cells.

PD-1 has two naturally occurring ligands, PD-L1 and PD-L2, which provide inhibitory signals to T cells through PD-1. αPD-1 blocks the inhibitory signal triggered by PD-L1 and PD-L2, while αPD-L1 only disrupts immunosuppression mediated by PD-L1. In theory, the anti-tumor effect of αPD-1 is expected to be better than αPD-L1. However, there is still no principle proof study comparing the effects of αPD-1 and αPD-L1 on tumor treatment. Furthermore, there are no indicators that predict whether patients will benefit more from αPD-1 or αPD-L1 therapy. Circulating TEV PD-L1 increases with tumor progression, which consumes a large amount of αPD-L1 but does not consume αPD-1. Therefore, TEV PD-L1 may weaken the therapeutic effect of αPD-L1, and circulating TEV PD-L1 may be a useful indicator for predicting the therapeutic outcomes of αPD-1 and αPD-L1, which remains to be explored.

Research process

02

Researchers found that TEV can effectively induce αPD-L1 through PD-L1. TEV-bound αPD-L1 is more easily engulfed by macrophages and then degraded more quickly by lysosomes. In this way, TEV consumes a large amount of αPD-L1, resulting in αPD-L1 not enough to block PD-L1 on tumor cells, thereby mediating αPD-L1 treatment resistance.

To prevent the side effects of increasing the therapeutic dose as much as possible, researchers attempted to develop better treatment strategies without changing the total therapeutic dose. They found that high-dose and low-frequency treatment with αPD-L1 was effectively overcome by using αPD-L1 treatment resistance in RAMP-C2 tumors at the same total therapeutic dose. Therefore, they believe that each sufficient dose of αPD-L1 treatment can more effectively induce antitumor immunity and establish antitumor immune memory. Anti-tumor immune memory lasts long and can prevent tumor recurrence. Therefore, even if the total treatment frequency is reduced, better anti-tumor effects can be achieved. They detected more memory T cells in TRAMP-C2 tumor-bearing mice treated with high-dose and low-frequency αPD-L1. Therefore, they developed an effective strategy to overcome αPD-L1 treatment resistance.

macrophages are the main effector cells mediating EV phagocytosis. The researchers found that macrophages cleared TEV-bound αPD-L1 faster than free αPD-L1. Depletion of macrophages by PLX3397 leads to dissociation of αPD-L1 from TEV and increases the blockade of tumor cells by PD-L1, thereby synergistically acting with αPD-L1, eliminating the therapeutic resistance of αPD-L1. Therefore, the use of in combination with PLX3397 is a promising strategy to overcome TEV-mediated resistance to αPD-L1 treatment . PLX3397 also improved the anti-tumor effect of αPD-1, but in contrast to the present study showing that PLX3397 promotes CD8 T-cell infiltration tumors, the researchers proposed that PLX3397 may enhance the anti-tumor effect of αPD-L1 by increasing the utilization of αPD-L1. The results show that the function of αPD-L1 is much more complex than the current model. However, the results also reveal that αPD-1 and αPD-L1 are not just substitutes for each other.

Research significance

03

clinical drug pexidartinib mediated increase in αPD-L1 dose or decrease in macrophages can all eliminate αPD-L1 treatment drug resistance . During the same treatment cycle as the total dose of αPD-L1 treatment, the anti-tumor effect of high-dose and low-frequency treatment is better than that of low-dose and high-frequency treatment, inducing stronger anti-tumor immune memory, and eliminating αPD-L1 treatment resistance. It is worth noting that in human xenograft tumor human immune system mice, increasing the dose of αPD-L1 and high and low frequency treatments both enhance the anti-tumor effect of αPD-L1.

In addition, increasing the dose of αPD-L1 and αPD-1 has similar anti-tumor effects, but αPD-L1 amplified PD-1+ Treg cells are less, and PD-1+ Treg cells are responsible for the high progression of tumors. In summary, the results of reveal TEVs-mediated αPD-L1-specific resistance mechanisms, thus providing a promising strategy for improving the efficacy of αPD-L1.

Reference materials:

https://www.nature.com/articles/s41423-022-00926-6

Note: This article aims to introduce the progress of medical research and cannot be used as a reference for treatment plans. If you need health guidance, please go to a regular hospital for treatment.

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