Non-canonical and induced neoantigens as emerging sources of cancer-specific immunotherapy targets

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Cancer immunotherapy has revolutionized treatment but shows limited efficacy in tumors with low mutational burden.
• Current immunotherapies primarily target neoantigens derived from tumor mutations.
• Expanding the range of targetable tumor-specific antigens is essential for broader clinical benefit.

Purpose of the Study:

• To review non-canonical and therapy-induced neoantigens as novel targets for cancer immunotherapy.
• To emphasize the potential of these neoantigens to improve current treatment approaches, particularly in challenging tumor types.
• To highlight the role of splicing dysregulation and chemotherapy in generating immunogenic neoepitopes.

Main Methods:

• Literature review focusing on non-canonical neoantigens (alternative splicing, RNA editing, transposable elements, aberrant translation).
• Analysis of evidence supporting the immunogenicity of neoepitopes derived from these sources.
• Examination of therapy-induced antigen generation, with a specific focus on chemotherapy-induced splicing alterations.

Main Results:

• Non-canonical sources like alternative splicing and RNA editing generate diverse neoantigens.
• Therapy-induced neoantigen generation, particularly via splicing alterations, represents a promising, underexplored immunotherapy strategy.
• These neoantigens show immunogenicity and potential for enhancing antitumor responses.

Conclusions:

• Integrating non-canonical and therapy-induced neoantigens can broaden immunotherapy applicability.
• These novel targets may significantly improve antitumor efficacy and specificity, especially in tumors with low mutational load.
• Further research into therapy-induced neoantigen generation is warranted to optimize cancer treatment.