GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE313nnn/GSE313967/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE313967GEOGSEfalseDecoy-resistant IL-18 therapy combined with anti-PD-1 induces CD4+ T cell-mediated elimination of murine β2M-deficient lung tumorsThough immune checkpoint inhibitors targeting the PD-1/PDL-1 axis have vastly improved patient outcomes in non-small cell lung cancer (NSCLC), both primary and acquired resistance limit their efficacy. Prior studies have identified partial or complete loss of MHC class I antigen presentation as a key driver of immunotherapy resistance in NSCLC. Here, we tested the efficacy of decoy-resistant IL-18 (DR-18) in combination with anti-PD-1 in several mouse models of NSCLC. DR-18 is a modified IL-18 cytokine that is not negatively regulated by IL-18 binding protein and has potential use for tumors that are refractory to immune checkpoint blockade. We found that 4 doses of DR-18 + anti-PD-1 slowed tumor growth in 3 of 4 β2M-deficient NSCLC models tested and resulted in complete elimination of a subset of tumors. Further mechanistic studies in the most sensitive UNSCC680 lung squamous carcinoma model revealed that therapy-mediated elimination was dependent upon CD4+ T cells and IFNγ. Immunophenotyping of UN-SCC680 tumors treated with DR-18 and anti-PD-1 revealed enrichment of activated CD4+ T cells, as well as the promotion of a pro-inflammatory transcriptional program across CD4+ T cell subsets and the enrichment of pro-inflammatory functions in tumor-infiltrating macrophages. Employing cytotoxicity assays with primary lymphocytes, we found that both CD4+ and CD8+ T cells, as well as NK cells, have the capacity to kill UN-SCC680 β2M-KO tumors. These results begin to reveal the role of CD4+ T cells in the coordination of MHC class I-independent mechanisms of tumor elimination that have the potential to be enhanced with DR-18 combined with anti-PD-1. This work highlights a potential strategy to overcome or avoid resistance caused by impaired MHC class I antigen presentation.2026/08/31GSE313967GSM9378646GSM9378647GSM9378644GSM937864524247313967Mus musculus