Signal Transduction and Targeted Therapy | Targeted Radioimmunotherapy Platform Targeting LRRC15 Effectively Combats Immunotherapy Resistance and Tumor Progression

This study develops a radioimmunotherapy platform targeting LRRC15, DUNP19, which combines radioactive isotopes for non-invasive imaging and efficient treatment. It effectively suppresses multiple solid tumor progressions and enhances the efficacy of immune checkpoint inhibitors, demonstrating broad clinical translational potential.

 

Literature Overview
This study, published in Signal Transduction and Targeted Therapy, titled 'Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance', reviews and summarizes LRRC15 as a cancer therapeutic target and evaluates the application of DUNP19 antibody in tumor targeting, imaging, and therapy. Based on LRRC15's high expression in TGFβ-driven tumor-associated fibroblasts and cancer cells with minimal expression in healthy tissues, the study develops a high-affinity, internalizing antibody coupled with radioactive isotopes for non-invasive tumor imaging and radioimmunotherapy. The research further assesses its therapeutic effects across multiple xenograft and syngeneic tumor models, revealing its capacity to clear TGFβ-driven resistance signaling pathways through transcriptomic analysis, providing theoretical support for subsequent combination therapies with immune checkpoint blockade.

Background Knowledge
LRRC15 (Leucine-Rich Repeat-Containing Protein 15) is a transmembrane protein induced by TGFβ, predominantly expressed in cancer cells and cancer-associated fibroblasts (CAFs) derived from mesenchymal stem cells but minimally in normal tissues, making it an ideal cancer target. Currently, immune checkpoint inhibitors (ICIs) have limited efficacy against multiple solid tumors, particularly those with immune-excluded tumor microenvironments. LRRC15+ CAFs have been proven to correlate with immune exclusion, treatment resistance, and disease aggressiveness. Therefore, LRRC15-targeted therapeutic strategies may remodel the tumor microenvironment, enhance immune cell infiltration, and improve ICI efficacy. DUNP19 is a fully human IgG1 monoclonal antibody with high affinity and rapid internalization capability, making it an optimal vehicle for radioimmunotherapy (RIT). When conjugated with Lutetium-177, this antibody effectively targets and eliminates LRRC15+ tumor and stromal cells while inducing DNA damage through cross-fire effects to kill surrounding antigen-negative cells. Additionally, the study demonstrates that RIT significantly reduces TGFβ-driven resistance signaling in the tumor transcriptome and achieves durable complete remission when combined with ICIs, offering novel solutions to immunotherapy resistance.

 

 

Research Methods and Experiments
Researchers developed a high-affinity, internalizing anti-LRRC15 monoclonal antibody, DUNP19, labeled with 64Cu or 177Lu for positron emission tomography (PET) imaging and radioimmunotherapy (RIT), respectively. The antibody's targeting specificity, biodistribution, therapeutic efficacy, and impact on tumor microenvironment were evaluated in multiple murine xenograft models. Transcriptomic analysis focused on gene expression changes related to TGFβ signaling, immune exclusion, and immune checkpoint blockade resistance post-RIT. Synergistic effects between DUNP19-RIT and anti-CTLA4/anti-PD1 antibodies were further assessed in syngeneic tumor models.

Key Conclusions and Perspectives

• DUNP19 rapidly internalizes upon LRRC15 binding, enabling precise radioisotope labeling for accurate targeting and high tumor uptake.
• [177Lu]Lu-DUNP19 significantly suppresses tumor growth and prolongs survival in multiple LRRC15+ tumor models with minimal toxicity.
• Transcriptomic analysis reveals substantial downregulation of TGFβ signaling pathways and pro-tumorigenic genes post-RIT, particularly those associated with immune checkpoint blockade resistance.
• In the HCC1954 breast cancer model, DUNP19-RIT effectively inhibits tumor growth by targeting LRRC15+ CAFs in the stroma.
• Syngeneic tumor models demonstrate that combining DUNP19-RIT with ICIs achieves durable complete remission, indicating its capacity to remodel immune-excluded microenvironments.

Research Significance and Prospects
This study introduces a novel radioimmunotherapy platform targeting LRRC15 with integrated diagnostic and therapeutic functionalities, enabling personalized tumor treatment and dose planning. The approach is particularly suitable for treating immune-excluded, therapy-resistant tumors. Future research should explore its clinical translational potential across diverse solid tumors and evaluate synergistic effects with various immunotherapy strategies.

 

 

Conclusion
This study successfully developed and validated a novel radioimmunotherapy platform, DUNP19, targeting LRRC15+ tumor and stromal cells. Conjugation with 177Lu enables effective tumor suppression while remodeling the tumor microenvironment by reducing TGFβ signaling and immune exclusion-related gene expression, thereby enhancing immune checkpoint inhibitor efficacy. The platform demonstrates favorable biodistribution and therapeutic effects across tumor models with controllable toxicity. Future applications may extend to preclinical studies in additional cancer types, providing new strategies for treating therapy-resistant malignancies.

 

Claire M Storey, Mohamed Altai, Katharina Lückerath, Daniel Thorek, and David Ulmert. Development of a leucine-rich repeat-containing protein 15-targeted radio-immunotheranostic approach to deplete pro-tumorigenic mechanisms and immunotherapy resistance. Signal Transduction and Targeted Therapy.