CD4⁺ T cells with convergent TCR recombination reprogram stroma and halt tumor progression in adoptive therapy

Cancers eventually kill hosts even when infiltrated by cancer-specific T cells. We examined whether cancer-specific T cell receptors of CD4⁺ T cells (CD4TCRs) from tumor-bearing hosts can be exploited for adoptive TCR therapy. We focused on CD4TCRs targeting an autochthonous mutant neoantigen that is only presented by stroma surrounding the MHC class II-negative cancer cells. The 11 most common tetramer-sorted CD4TCRs were tested using TCR-engineered CD4⁺ T cells. Three TCRs were characterized by convergent recombination for which multiple T cell clonotypes differed in their nucleotide sequences but encoded identical TCR α and β chains. These preferentially selected TCRs destroyed tumors equally well and halted progression through reprogramming of the tumor stroma. TCRs represented by single T cell clonotypes were similarly effective only if they shared CDR elements with preferentially selected TCRs in both α and β chains. Selecting candidate TCRs on the basis of these characteristics can help identify TCRs that are potentially therapeutically effective.