Many patients remain unresponsive to intensive PD-1/PD-L1 blockade therapy despite the presence of tumor-infiltrating lymphocytes. We propose that impaired innate sensing might limit the complete activation of tumor-specific T cells after PD-1/PD-L1 blockade. Local delivery of type I interferons (IFNs) restores antigen presentation, but upregulates PD-L1, dampening subsequent T-cell activation. Therefore, we armed anti-PD-L1 antibody with IFNα (IFNα-anti-PD-L1) to create feedforward responses. Here, we find that a synergistic effect is achieved to overcome both type I IFN and checkpoint blockade therapy resistance with the least side effects in advanced tumors. Intriguingly, PD-L1 expressed in either tumor cells or tumor-associated host cells is sufficient for fusion protein targeting. IFNα-anti-PD-L1 activates IFNAR signaling in host cells, but not in tumor cells to initiate T-cell reactivation. Our data suggest that a next-generation PD-L1 antibody armed with IFNα improves tumor targeting and antigen presentation, while countering innate or T-cell-driven PD-L1 upregulation within tumor.

IL-15 is a promising cytokine to expand NK and CD8 + T cells for cancer immunotherapy, but its application is limited by doselimiting, on-target off-tumor toxicity. Here, we have developed a next-generation IL-15 that is activated inside the tumor microenvironment (TME). This pro-IL-15 has the extracellular domain of IL-15Rβ fused to the N-terminus of sIL-15-Fc through a tumor-enriched Matrix Metalloproteinase (MMP) cleavable peptide linker to block its activity. Unlike sIL-15-Fc, pro-IL-15 does not activate the peripheral expansion of NK cells and T cells, thus reducing systemic toxicity, but it still preserves efficient anti-tumor abilities. In various mouse tumors, the anti-tumor effect of pro-IL-15 depends on intratumoral CD8 + T cells and IFN-γ. Pro-IL-15 increases the stem-like TCF1 + Tim-3 − CD8 + T cells within tumor tissue and helps overcome immune checkpoint blockade (ICB) resistance. Moreover, pro-IL-15 synergizes with current tyrosine kinase inhibitor (TKI) targeted-therapy in a poorly inflamed TUBO tumor model, suggesting that pro-IL-15 helps overcome targeted-therapy resistance. Our results demonstrate a next-generation IL-15 cytokine that can stimulate potent anti-tumor activity without severe toxicity.

Objectives: LncRNAs are essential survival prognostic indicators with important biological functions in tumorigenesis and tumor progression. This study aimed to establish a long non-coding RNA (lncRNA) signature that can effectively predict the prognosis of patients with head and neck squamous cell carcinoma (HNSCC) and explore the potential functions of these lncRNAs.Materials and Methods: We re-annotated RNA sequencing and obtained exhaustive RNA-seq data of 269 patients with comprehensive clinical information from the GEO database. Then an 8-lncRNA signature capable of predicting the survival prognosis of HNSCC patients and a nomogram containing this signature were established. Weighted Co-expression Network Construction (WGCNA), Gene Set Enrichment Analysis (GSEA), and Gene Ontology (GO) enrichment were then applied to predict the possible biological functions of the signature and each individual lncRNA.Results: Eight lncRNAs associated with survival in HNSCC patients, including AC010624.1, AC130456.4, LINC00608, LINC01300, MIR99AHG, AC008655.1, AC055758.2, and AC118553.1, were obtained by univariate regression, cox LASSO regression, and multivariate regression. Functionally, patients with high signature scores had abnormal immune functions via GSEA. AC010624.1 and AC130456.4 may participate in epidermal cell differentiation and skin development, and MIR99AHG in the formation of cellular structures. Other lncRNAs in the signature may also participate in important biological processes.Conclusions: Therefore, we established an 8-lncRNA signature that can effectively guide clinical prediction of the prognosis of patients with HNSCC, and individuals with high signature scores may have abnormal immune function.