A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice

Area of Science:

• Immunology
• Oncology
• T cell biology

Background:

• T cell immunotherapy, particularly with engineered high-affinity T cell receptors (TCRs), shows potential for improved tumor regression.
• The critical role of T cell subsets expressing these high-affinity TCRs in controlling tumor growth remains incompletely understood.

Purpose of the Study:

• To investigate whether a high-affinity TCR alone is sufficient for tumor control or if the T cell subset expressing it is also crucial.
• To develop and characterize a novel TCR transgenic mouse model expressing a human tyrosinase epitope-reactive, CD8-independent, high-affinity TCR.

Main Methods:

• Isolation of a high-affinity TCR from tumor-infiltrating lymphocytes (TIL) of a metastatic melanoma patient.
• Development of a TCR transgenic mouse model on a C57BL/6 background, expressing an HLA-A2-restricted TCR.
• Analysis of TCR expression in different T cell subsets (CD4+, CD8+, and double-negative) and assessment of their in vivo functionality and tumor control capabilities.

Main Results:

• The transgenic TCR was primarily expressed by double-negative T cells (CD3+CD4-CD8-) in HLA-A2 background mice.
• TIL 1383I TCR transgenic T cells (CD4+, CD8+, and double-negative) demonstrated functionality and controlled tumor growth in vivo without adjuvant therapy.
• HLA-A2(+)/human tyrosinase TCR double-transgenic mice exhibited age-progressive hair depigmentation and visual defects.

Conclusions:

• Expression of the high-affinity TIL 1383I TCR in CD3+ T cells is sufficient for controlling both murine and human melanoma growth.
• The presence or absence of CD4 and CD8 coreceptors has minimal impact on the functional capacity of T cells expressing this high-affinity TCR.