Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti–PD-1 immunotherapy

Abstract

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome–heat shock protein 70 (HSP70) signaling axis is triggered by CD8 + T cell cytotoxicity and contributes to the development of adaptive resistance to anti–programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti–PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti–PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti–PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti–PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.

Gli2 Facilitates Tumor Immune Evasion and Immunotherapeutic Resistance by Coordinating Wnt Ligand and Prostaglandin Signaling

“…Previously, we have shown that Wnt5a signaling induces CD45 + CD11b + Ly6G + Ly6C lo F4/80 - PMN-MDSC recruitment via autocrine stimulation of CXCR2-dependent chemokines and that their presence is inversely related to CD8 + T cell infiltration [36]. In further studies, we have shown this PMN-MDSC population to suppress CD8 + T cell expansion in vitro and in vivo [7]. Indeed, consistent with these findings, flow cytometry demonstrated a substantial increase in PMN-MDSCs in BRAF V600E PTEN −/− Gli2 CA tumors as well as in the tumor-draining lymph nodes (TDLN) relative to controls ( Figure 2G, Supplemental Figure 2E ).…”

“…More recently, we have associated the immune evasive state of MT with tumor-expressed Wnt ligands, and further demonstrated that Wnt ligand inhibition can overcome anti-PD-1 resistance in autochthonous models of melanoma and non-small cell lung cancer [5]. In addition, our prior studies have implicated Wnt5a as particularly important in establishing a tolerogenic state, including tumor-mediated dendritic cell (DC) tolerization as well as the recruitment of granulocytic myeloid-derived suppressor cells (PMN-MDSCs) into the tumor bed [5–7]. PMN-MDSCs are a population of immature myeloid cells which are trafficked to the tumor bed via a CXCR2 chemokine gradient, where they produce suppressive mediators including TGFβ and nitric oxide (NO) to mitigate anti-tumor T cell responses and promote metastasis [8–11].…”

The Educational Program of Macrophages toward a Hyperprogressive Disease-Related Phenotype Is Orchestrated by Tumor-Derived Extracellular Vesicles

“…It is also plausible to speculate that other tumor intrinsic factors may dictate the ability of cancer cells to induce HPD even through macrophage reprogramming. For instance, it was recently demonstrated that, in tumor cells, NLRP3 signaling, a key player of the inflammasome pathway [ 30 ], can trigger HPD after anti-PD1 antibody administration [ 31 ]. We next investigated the phenotype acquired by macrophages after exposure to the different NSCLC cell line CMs.…”

Harnessing innate immune pathways for therapeutic advancement in cancer

“… 346 , 347 Activation of epithelial TLR4 also fosters the recruitment of PMN-MDSCs, setting the stage for pre-metastatic niches. 348 Furthermore, activation of TLR4 in M2 TAMs can induce EMT in pancreatic cancer cells partially through IL-10 signaling. 349 In lung epithelial cells, TLR3 can be activated by RNA from exosomes derived from primary tumors.…”