Improving PD-1 blockade plus chemotherapy for complete remission of lung cancer by nanoPDLIM2

Background Immune checkpoint inhibitors (ICIs) and their combination with other therapies such as chemotherapy, fail in most cancer patients. We previously identified the PDZ-LIM domain-containing protein 2 (PDLIM2) as a bona fide tumor suppressor that is repressed in lung cancer to drive cancer and its chemo and immunotherapy resistance, suggesting a new target for lung cancer therapy improvement. Methods Human clinical samples and data were used to investigate PDLIM2 genetic and epigenetic changes in lung cancer. Using an endogenous mouse lung cancer model faithfully recapitulating refractory human lung cancer and a clinically feasible nano-delivery system, we investigated the therapeutic efficacy, action mechanism, and safety of systemically administrated PDLIM2 expression plasmids encapsulated in nanoparticles (nanoPDLIM2) and its combination with PD-1 antibody and chemotherapeutic drugs. Results PDLIM2 repression in human lung cancer involves both genetic deletion and epigenetic alteration. NanoPDLIM2 showed low toxicity, high tumor specificity, antitumor activity, and greatly improved the efficacy of anti-PD-1 and chemotherapeutic drugs, with complete tumor remission in most mice and substantial tumor reduction in the remaining mice by their triple combination. Mechanistically, nanoPDLIM2 increased major histocompatibility complex class I (MHC-I) expression, suppressed multi-drug resistance 1 (MDR1) induction and survival genes and other tumor-related genes expression in tumor cells, and enhanced lymphocyte tumor infiltration, turning the cold tumors hot and sensitive to ICIs and rendering them vulnerable to chemotherapeutic drugs and activated tumor-infiltrating lymphocytes (TILs) including those unleashed by ICIs. Conclusions These studies established a clinically applicable PDLIM2-based combination therapy with great efficacy for lung cancer and possibly other cold cancers. ### Competing Interest Statement The authors have declared no competing interest. * AC : adenocarcinoma BFA : brefeldin A CNV : copy number variation CTL : cytotoxic T lymphocyte FACS : fluorescent activated cell sorting FDA : Food and Drug Administration IFNγ : interferon-γ ICD : immunogenic cell death ICI : immune checkpoint inhibitor IHC : immunohistochemistry i.p. : intraperitoneal i.v. : intravenous LOH : loss of heterozygosity MDR1 : multi-drug resistance 1 MHC-I : major histocompatibility complex class I nanoPDLIM2 : nanoparticle-encapsulated PDLIM2-expression plasmids NF-κB : nuclear factor-κB NIH : National Institutes of Health ORR : objective response rate OS : overall survival PD-1 : programmed cell death 1 PD-L1 : programmed death ligand 1 PD-L2 : programmed death ligand 2 PDLIM2 : PDZ-LIM domain-containing protein 2 PEI : polyethylenimine PFS : progression-free survival PMA : phorbol 12-myristate 13-acetate qPCR : quantitative polymerase chain reaction SEM : standard error of the mean STAT3 : signal transducer and activator of transcription 3 TCGA : The Cancer Genome Atlas TIL : tumor-infiltrating lymphocyte WT : wild type.