Biology subjects

Akilli, O.

Publications and source records attributed to Akilli, O..

2 recordsLinked to original sources

bioRxiv2026

Mapping the immune landscape in small cell lung cancer unveils a distinct tumor-reactive CD8+ T cell molecular signature

Small cell lung cancer (SCLC) is a highly aggressive malignancy with limited therapeutic advances. Unlike many other cancers, its immune landscape, particularly immune competence and T cell recognition, remains poorly characterized. Here, we generate a single-cell transcriptome atlas of the SCLC immune microenvironment with paired T cell receptor (TCR) sequencing. By linking T cell states with clonality and a multilayered functional screening, we identify 6 tumor-reactive TCRs that recognize and eradicate autologous SCLC cell lines. We delineate a novel SCLC-reactive CD8+ T cell signature (SCLC_TR), enabling the identification of 47 further SCLC-reactive TCRs. The SCLC_TR signature performs extremely well in pancreatic ductal adenocarcinoma (PDAC), another immune-cold tumor indication, and, most strikingly, patients with elevated SCLC_TR signature scores exhibited significantly improved survival, underlining its prognostic potential. Comparative cell-cell interaction analyses implicate several immunosuppressive mechanisms, with myeloid cells and CD4 regulatory T cells possibly acting as counterbalances to effector T cell activity in SCLC. In summary, our study challenges the prevailing notion of SCLC as an immune-cold tumor type by providing direct evidence of tumor-reactive T cell responses and introduces the SCLC_TR signature as a tool to identify tumor-specific T cells and their microenvironmental restraints and escape mechanisms, ultimately shaping next-generation immunotherapeutic strategies. O_FIG O_LINKSMALLFIG WIDTH=195 HEIGHT=200 SRC="FIGDIR/small/735200v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1c25f2eorg.highwire.dtl.DTLVardef@1f6f519org.highwire.dtl.DTLVardef@553e57org.highwire.dtl.DTLVardef@6fe7e1_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2026

Lung-targeted cytokine-coding RNA-lipoplexes induce T and NK cell-mediated anti-tumor immune response

Lung is a major site of metastases for many primary cancers associated with poor outcomes. A central challenge in cancer immunotherapy is overcoming tumor immune evasion, which limits effective antitumor responses. Here, we investigated whether combinatorial mRNA-encoded cytokine therapy can overcome tumor immune evasion by coordinately engaging innate and adaptive immunity, using murine models of pulmonary metastases. We employed intravenously administered cationic nucleoside-modified mRNA-lipoplexes (RNA-LPX) for targeted delivery of mRNA-encoded cytokines to the lung. The cytokine mix containing interferon-, half-life extended interleukin (IL)-7, and a half-life extended IL-2 variant with reduced CD25-binding modulated the tumor immune microenvironment resulting in a potent and broad anti-tumor response and prolonged survival with good tolerability at the conditions tested. Using cell depletion experiments, we demonstrated that both T and natural killer (NK) cells are crucial mediators of the observed anti-tumor efficacy of the cytokine RNA mix, which induced activation and effector function of NK and T cells, coupled with reduced regulatory T cells (Treg) numbers and Treg activation in the lung. Importantly, antitumor efficacy was maintained in models of impaired antigen presentation, including loss of an immunodominant tumor antigen and MHC class I deficiency, where NK cells served as the primary effectors. The cytokine RNA mix induced immune cell activation in the primary human lung tumor culture, suggesting potential for translational application. Collectively, these findings demonstrate that combinatorial cytokine therapy can drive both antigen-dependent and antigen-independent tumor control for the treatment of lung metastases.

immunology↗