Chimeric MHC class I- and II-restricted non-self epitopes broaden antitumor T cell reactions

Area of Science:

• Immunology
• Cancer Biology
• Molecular Biology

Background:

• The mechanism of how one non-self antigen enhances T cell responses to another is not fully understood.
• Immune responses can be augmented by chimeric non-self peptides, termed complete T cell antigens (CTAs).

Purpose of the Study:

• To investigate the role of CTAs in augmenting T cell immune responses.
• To elucidate the mechanism by which CTAs enhance antitumor immunity.
• To explore the clinical relevance of CTAs in cancer prognosis and therapy.

Main Methods:

• Identification and characterization of complete T cell antigens (CTAs) as single-chain chimeras with MHC class I- and II-restricted epitopes.
• Administration of CTAs as live cell adjuvants or via cDNA-transfected muscle to assess T cell reactivity against tumor neoantigens.
• Analysis of dendritic cell phenotype, CD8+ T cell exhaustion, and CD8+ T cell generation in tumors following CTA treatment.
• Correlation of CTA expression in cancers with frameshift mutations to patient prognosis and response to PD-1 blockade therapy.

Main Results:

• CTAs, when administered, increased T cell reactivity against tumor neoantigens, even if unrelated to tumor antigens.
• CTA treatment modulated dendritic cell phenotype in a CD4+ T cell-dependent manner.
• CTA administration suppressed CD8+ T cell exhaustion and promoted the generation of self-renewing CD8+ T cells within tumors.
• Cancers with frameshift mutations, often containing CTAs, showed improved prognosis and better response to PD-1 blockade therapy in preclinical and clinical settings.

Conclusions:

• CTAs are sufficient to induce overall antitumor immunity by broadening T cell responses to other neoantigens.
• The expression of CTAs in a subset of cancer cells can evoke a broader antitumor immune response.
• CTAs represent a potential therapeutic strategy for enhancing cancer immunotherapy by overcoming T cell exhaustion and improving treatment outcomes.