Concern! PD-1 immune blockade promotes the drive of tumor NLRP3-HSP70-TLR4 axis to pre-metastasis niche/tumor hyperprogression

A proportion of melanoma patients who receive PD-1 blockade experience hyperprogression, meaning that the disease progresses more rapidly
after treatment.
Theivanthiran, a researcher from Duke University Medical Center, et al.
revealed the mechanism by
which this phenomenon occurs.
The authors found that the NLRP3-HSP70-TLR4 signaling axis drives the development of the pre-metastasis microenvironment in the lungs of melanoma mice, and PD-1 blockade further enhances this process
.
These in vivo observations are consistent with what the authors observed in melanoma patients, suggesting that tumor NLRP3 activity is associated with
hyperprogression in melanoma patients.
Gene ablation or drug inhibition of this signaling axis can inhibit metastasis in mice, suggesting that this signaling axis is worthy of further study
as a clinical target.

The tumor's intrinsic NLRP3-HSP70-TLR4 (NOD, LRR, and pyrin domains contain protein 3 (NLRP3) inflammasome-heat shock protein 70 (HSP70)) signaling axis is triggered by CD8⁺ T cells and enters the tumor microenvironment by recruiting "granulocyte polymorphonuclear myeloidal myeloid-derived suppressor cells (PMN-MDSCs)".
Promotes adaptive resistance
to anti-PD-1 immunoblockade therapy.
The study showed that the tumor NLRP3-HSP70 axis also drove the accumulation of "granulocyte polymorphonuclear myeloidal inhibitory cell PMN-MDSCs" into distant lung tissues in a manner that relied on Toll-like receptor 4 (TLR4) signaling in lung epithelial cells, thereby establishing a pre-metastatic niche that supported disease progression
after anti-PD-1 immunotherapy.
The pulmonary epithelial HSP70-TLR4 signaling pathway promotes myeloid granulocyte production and recruitment of PMN-MDSCs into lung tissue
by inducing downstream Wnt5a-dependent granulocyte colony-stimulating factor (G-CSF) and chemokine ligand 5 (CXCL5).
Anti-PD-1 immunotherapy enhances the activation of this pathway through immune stress and drives disease progression
in the case of Nlrp3 amplification.

In preclinical models of melanoma and breast cancer, gene and drug inhibition of NLRP3 and HSP70 blocks the aggregation of PMN-MDSCs in the lungs after anti-PD-1 therapy and inhibits metastatic progression
.
In patients with stage IV melanoma receiving anti-PD-1 immunotherapy, an increase in the baseline concentration of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue samples correlated
with hyperprogression and poor survival of the disease.

In conclusion, this work reveals the pathogenic mechanism of the phenomenon of hyperprogression of melanoma disease and provides candidate targets and markers that can improve the management of melanoma patients
.