One CD4+TCR and One CD8+TCR Targeting Autochthonous Neoantigens Are Essential and Sufficient for Tumor Eradication

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Adoptive T-cell receptor (TCR) therapy shows promise for cancer treatment.
• Solid tumors present challenges due to heterogeneity and neoantigen expression.
• Understanding the optimal T-cell subsets and targets is crucial for effective TCR therapy.

Purpose of the Study:

• To determine the necessary number and types of neoantigens and T-cell receptors (TCRs) for solid tumor eradication.
• To evaluate the efficacy of different T-cell subsets (CD4+ and CD8+) in TCR therapy against heterogeneous tumors.

Main Methods:

• Utilized autochthonous (naturally occurring) neoantigens in established solid tumors.
• Employed adoptive transfer of TCR-engineered autologous T cells (TCR-therapy).
• Compared CD8+TCR-therapy, CD4+TCR-therapy, and combination therapies against heterogeneous and homogenous tumors.

Main Results:

• CD8+TCR-therapy alone frequently led to relapse in heterogeneous tumors.
• Combination therapy of CD8+ and CD4+ TCR-therapy eradicated large, established heterogeneous tumors.
• CD4+TCR-therapy targeted tumor stroma, while CD8+TCR-therapy was vital for direct cancer cell recognition.

Conclusions:

• Two cancer-specific TCRs targeting autochthonous neoantigens are sufficient for eradicating heterogeneous solid tumors.
• Simplifications in adoptive TCR-therapy are possible without sacrificing efficacy.
• Combination CD4+ and CD8+ TCR-therapy offers a potent strategy against complex solid tumors.