Background Despite having a significant impact on cancer patients, many questions remain regarding both the pathogenesis and management of many immune-related adverse events (irAEs). We are unable to predict which patients will develop more severe irAEs and our current protocols for managing these conditions remain potentially detrimental to clinical outcomes. We have shown that the tumor-intrinsic NLRP3-HSP70 signaling axis modulates neutrophil recruitment and accumulation in distant tissues. Genetic amplification of NLRP3 is commonly observed in several solid tumor types.
Methods Micro-PET CT imaging, endoscopic tissue biopsies, immunofluorescence microscopy, single-cell RNAseq (scRNAseq) transcriptional profiling, and multi-parameter flow cytometry were used to characterize the development of inflammatory colitis and pneumonitis in transgenic tumor models in response to anti-PD-1 immunotherapy. Clinical tumor tissue and plasma specimens were collected from melanoma patients undergoing checkpoint inhibitor immunotherapy and NLRP3-ASC proximity ligation assays, NLRP3 FISH, and HSP70 ELISAs were performed and correlated with the development of irAEs.
Results We observed that inflammatory colitis and pneumonitis was only recognized in tumor-bearing mice administered anti-PD-1 immunotherapy, while non-tumor bearing mice failed to develop any evidence of these irAEs while undergoing the same treatment regimen. Interestingly, similar irAE findings were also noted in mice following primary tumor resection and adjuvant anti-PD-1 immunotherapy. Characterization of these colon and lung tissues revealed evidence of early tumor-dependent PD-11 neutrophil infiltration prior to anti-PD-1 immunotherapy followed by IL-1b-dependent accumulation of TH17 cells upon PD-1 blockade. Genetic ablation of the tumor-intrinsic NLRP3 inflammasome as well as HSP70 blockade reverses this process. A NLRP3 inhibitor eliminates anti-PD-1-associated colitis and pneumonitis while demonstrating superior anti-tumor control relative to prednisone. Tumors harboring Nlrp3 amplification exhibit enhanced severity of colitis and pneumonitis in response to PD-1 blockade and are more refractory to prednisone therapy. Baseline tumor NLRP3 amplification levels, NLRP3 signaling activation levels, as well as plasma HSP70 levels correlate with incidence and grade of colitis as well as the number of irAEs in stage IV (96) and III melanoma (25) patients (P<0.05). scRNAseq/scATACseq studies of bone marrow neutrophil progenitor populations in tumor-bearing mice demonstrate evidence of tumor-associated, NLRP3-dependent epigenetic and transcriptional re-programming consistent with innate training.
Conclusions Tumor-mediated re-programming of neutrophil progenitors facilitates the development of inflammatory colitis and pneumonitis in response to anti-PD-1 immunotherapy. The tumor-intrinsic NLRP3-HSP70 signaling axis primes neutrophil populations for enhanced pathologic responses to anti-PD-1 immunotherapy and provides both pharmacologic targets and biomarkers capable of improving the management of irAEs in cancer patients.
Theivanthiran B, Yarla N, Haykal T, Cao L, Ferreira M, Plebanek M, Holtzhausen A, Al-Rohil R, Salama AKS, Beasley GM, DeVito NC, Hanks BA. The Tumor-Intrinsic NLRP3 Inflammasome Promotes Melanoma Metastases via HSP70-TLR4 Activation and Facilitates Disease Hyperprogression following Anti-PD-1 Immunotherapy. Science Translational Medicine. 2022;14:eabq7019.
Ethics Approval All patients provided written informed consent under an IRB-approved protocol at Duke University Medical Center and the Duke Cancer Institute (Pro00090678).
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