Self-antigen-specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response

Area of Science:

• Immunology
• Cancer Research
• Vaccinology

Background:

• Cancer immunotherapy aims to enhance anti-tumor immune responses.
• Ineffective cancer vaccines may result from insufficient self-reactive lymphocytes after negative selection.
• The frequency of CD8(+) T cells recognizing self-antigens is extremely low (<0.0001%).

Purpose of the Study:

• To investigate the impact of CD8(+) T cell precursor frequency on tumor immunity and autoimmunity.
• To determine if supplementing T cell repertoires can improve vaccine efficacy.
• To identify optimal conditions for T cell transfer in cancer immunotherapy.

Main Methods:

• Estimation of CD8(+) T cell precursor frequency recognizing a specific self-antigen in mice.
• Transfer of varying numbers of naive antigen-specific T cells.
• Assessment of vaccine-elicited tumor immunity and autoimmunity.
• Analysis of T cell proliferation, polyfunctionality, and tumor eradication in irradiated hosts.

Main Results:

• Very low precursor frequencies (<0.0001%) limit anti-tumor immune responses.
• Supplementing T cells improved immunity but impaired function above a competitive threshold due to intraclonal competition.
• T cells primed below the competitive threshold showed enhanced proliferation, polyfunctionality, and tumor eradication.

Conclusions:

• CD8(+) T cell precursor frequency is functionally relevant to tumor immunity and autoimmunity.
• Transferring optimized numbers of naive tumor-specific T cells with in vivo activation is a promising approach for human cancer immunotherapy.
• Precursor frequency can be manipulated to improve the efficacy of clinical cancer vaccine strategies.