InVivoMAb anti-mouse PD-L1 (B7-H1)

The PD-1/PD-L1 axis represents a well-established immunotherapeutic target. Nevertheless, anti-PD-1/PD-L1 therapeutics have shown limited efficacy in the management of solid tumors, particularly in the context of hepatocellular carcinoma (HCC). Among the various factors contributing to the resistance to anti-PD-1/PD-L1 therapy, tumor-associated macrophages (TAMs) have attracted significant interest because of the immunosuppressive properties. NPLOC4 has been explored as an antitumor drug target. However, whether NPLOC4 functions in TAMs or immunotherapy is unclear. Here, we report a new role for NPLOC4+ TAMs in inhibiting antitumor immune responses by facilitating the proteasomal degradation of RIG-I. Clinical specimens revealed that the number of NPLOC4+ TAMs are negatively correlated with the prognosis of patients with HCC. Proteomic data and in vitro/in vivo experiments demonstrated that NPLOC4 inhibits the type I interferon pathway in TAMs, promotes M2 polarization, and suppresses CD8+ T-cell infiltration, thereby creating an immunosuppressive microenvironment in HCC. NPLOC4 can bind to RIG-I and mediate its ubiquitination-mediated degradation, thus suppressing the type I interferon pathway. Animal studies have indicated that disulfiram/copper (DSF/Cu) can target the NPLOC4 protein, and that the combination of DSF/Cu with PD-1 therapy significantly inhibits HCC growth. In conclusion, targeting NPLOC4+ TAMs can significantly increase the resistance of HCC to anti-PD-1 therapy, which makes it a promising novel immune target for HCC treatment.

Conventional chemotherapeutic agents, such as 5-fluorouracil (5-FU), can exert anti-tumor effects through immunogenic cell death (ICD) induction. Researchers have found hallmarks that quantify ICD (such as the translocation of HMGB1 and calreticulin). Although chemotherapeutic agents can induce ICD, they increase the expression of immune checkpoints, limiting their effectiveness. Studies have emphasized the importance of investigating the heterogeneous responses of cells co-localized in a solid tumor (macrophages, tumor cells, etc.) to ICD induction. However, these studies were performed in vivo, which limits the collection of information on cell-cell interactions due to model complexity.

Immune exhaustion corresponds to a loss of effector function of T cells that associates with cancer or chronic infection. Here, our objective was to decipher the mechanisms involved in the immune suppression of myeloid-derived suppressor cells (MDSCs) and to explore the potential to target these cells for immunotherapy to enhance checkpoint blockade efficacy in a chronic parasite infection. We demonstrated that programmed cell-death-1 (PD-1) expression was significantly upregulated and associated with T-cell dysfunction in advanced alveolar echinococcosis (AE) patients and in Echinococcus multilocularis-infected mice. PD-1 blockade ex vivo failed to reverse AE patients' peripheral blood T-cell dysfunction. PD-1/PD-L1 blockade or PD-1 deficiency had no significant effects on metacestode in mouse model. This was due to the inhibitory capacities of immunosuppressive granulocytic MDSCs (G-MDSCs), especially in the liver surrounding the parasite pseudotumor. MDSCs suppressed T-cell function in vitro in an indoleamine 2, 3 dioxygenase 1 (IDO1)-dependent manner. Although depleting MDSCs alone restored T-cell effector functions and led to some limitation of disease progression in E. multilocularis-infected mice, combination with PD-1 blockade was better to induce antiparasitic efficacy. Our findings provide preclinical evidence in support of targeting MDSC or combining such an approach with checkpoint blockade in patients with advanced AE. (200 words).

Pancreatic ductal adenocarcinoma (PDAC) is characterised by immune evasion that contribute to poor prognosis. Cancer-associated fibroblasts (CAFs) play a pivotal role in orchestrating the PDAC tumour microenvironment. We investigated the role of CAF-derived extracellular vesicle (EV)-packaged long non-coding RNAs (lncRNAs) in immune evasion and explored gene therapy using engineered EVs loading small interfering RNAs (siRNAs) as a potential therapeutic strategy. Our findings highlight the significance of EV-packaged lncRNA RP11-161H23.5 from CAF in promoting PDAC immune evasion by downregulating HLA-A expression, a key component of antigen presentation. Mechanistically, RP11-161H23.5 forms a complex with CNOT4, a subunit of the mRNA deadenylase CCR4-NOT complex, enhancing the degradation of HLA-A mRNA by shortening its poly(A) tail. This immune evasion mechanism compromises the anti-tumour immune response. To combat this, we propose an innovative approach utilising engineered EVs as natural and biocompatible nanocarriers for siRNA-based gene therapy and this strategy holds promise for enhancing the effectiveness of immunotherapy in PDAC. Overall, our study sheds light on the critical role of CAF-derived EV-packaged lncRNA RP11-161H23.5/CNOT4/HLA-A axis in PDAC immune evasion and presents a novel avenue for therapeutic intervention.