Treatment with mRNA coding for the necroptosis mediator MLKL induces antitumor immunity directed against neo-epitopes

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Cancer immunotherapy offers durable antitumor responses but faces challenges with patient response rates.
• Developing novel strategies to overcome therapeutic resistance is crucial for improving cancer treatment outcomes.

Purpose of the Study:

• To investigate the efficacy of intratumor delivery of mRNA encoding the necroptosis executioner mixed lineage kinase domain-like (MLKL) protein as a novel cancer immunotherapy.
• To evaluate the potential of MLKL-mRNA therapy, alone and in combination with immune checkpoint blockade, in preclinical cancer models.

Main Methods:

• Intratumor administration of mRNA encoding MLKL in syngeneic mouse melanoma and colon carcinoma models.
• Assessment of primary tumor growth, distal and disseminated tumor formation, and immune responses.
• Evaluation of combination therapy with immune checkpoint blockade.
• Analysis of T cell responses, type I interferon signaling, and Batf3-dependent dendritic cells.
• Testing in human lymphoma xenograft models with reconstituted human adaptive immune systems.

Main Results:

• MLKL-mRNA treatment effectively stalled primary tumor growth and prevented distal and disseminated tumor formation in mouse models.
• Combination of MLKL-mRNA with immune checkpoint blockade significantly enhanced antitumor activity.
• The therapy rapidly induced T cell responses against tumor neo-antigens, requiring CD4+ and CD8+ T cells.
• Type I interferon signaling and Batf3-dependent dendritic cells were essential for eliciting tumor antigen-specific T cell responses.
• MLKL-mRNA treatment demonstrated efficacy against human lymphoma in immunocompromised mouse models.

Conclusions:

• Intratumor delivery of MLKL-encoding mRNA represents a promising generic antitumor immunotherapy.
• This approach can synergize with immune checkpoint blockade to improve therapeutic outcomes.
• The therapy leverages innate and adaptive immune mechanisms, including T cell responses and specific dendritic cell subsets.