Targeting ZDHHC9 potentiates anti-programmed death-ligand 1 immunotherapy of pancreatic cancer by modifying the tumor microenvironment

Abstract Background Immune checkpoint blockade (ICB) therapy targeting the programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has achieved considerable success in treating a wide range of cancers. However, most patients are still resistant to ICB and lack of optimal biomarkers to predict response. Thus, uncovering the underlying cellular and molecular determinants of ICB resistance is needed to improve the efficacy of anti-PD-1/L1 therapy. Palmitoylation is mediated by a family of 23 S-acyltransferases, Asp-His‐His‐Cys type (ZDHHC) palmitoyltransferases, that precisely control various cancer-related protein functions, representing promising drug targets for cancer therapy. However, how specific ZDHHC palmitoyltransferases affect the tumour microenvironment (TME) and augment the therapeutic efficacy of ICB remains elusive. Methods Five syngeneic subcutaneous tumour models were used to demonstrate the anti-tumour activity of ZDHHC9 deficiency. Multispectral flow cytometry was used to characterize alterations in immune cell subsets. Two poorly immunogenic tumour models were used to evaluate the synergistic effect of ZDHHC9 deficiency and anti-PD-L1 therapy. A polymeric nanoparticle approach was developed for the in vivo delivery of ZDHHC9-siRNA to tumour tissues. The TGCA database was used to assess the expression pattern and immunological characteristics of ZDHHC9 in pan-cancers. Results We found that tumor cell-intrinsic “immuno-oncogene” Zinc Finger DHHC-Type Containing 9 (ZDHHC9) was overexpressed in various human cancers and associated with impaired anti-tumor immunity. In five syngeneic tumour models, the knockdown of ZDHHC9 expression in tumour cells was sufficient to suppress tumour progression and improve survival by reprogramming the immunosuppressive (‘cold’) to proinflammatory (‘hot’) TME. Furthermore, ZDHHC9 deficiency in tumour cells sensitized anti-PD-L1 immunotherapy in CD8+ T cells dependent manner. Lastly, we employed the ZDHHC9-siRNA nanoparticle system to efficiently silence ZDHHC9 in tumours whilst potentiating anti-PD-L1 immunotherapy in non-immunogenic tumours. Conclusion Tumour-intrinsic S-palmitoylation regulator ZDHHC9 tumour expression is a mechanism of inhibition of host anti-tumour immunity and reprogramming of immunosuppressive tumour microenvironment. Inactivating ZDHHC9 highlights an effective immunotherapeutic strategy and booster for anti-PD-L1 therapy.