Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• T cells targeting cancer neoantigens are crucial for antitumor immunity.
• Many cancers have limited mutations, posing challenges for neoantigen-based therapies.
• Adoptive cell transfer of tumor-infiltrating lymphocytes (TILs) is a promising cancer treatment.

Purpose of the Study:

• To investigate the T cell response in a patient with stage IV acral melanoma achieving complete response after TIL therapy.
• To identify the specific targets of TILs, particularly in a low-mutation-burden cancer.
• To explore the potential of targeting the BRAFV600E mutation with engineered T cells.

Main Methods:

• Whole exome sequencing of tumor tissue.
• T cell receptor (TCR) sequencing and specificity analysis of TILs and peripheral blood.
• Gene transfer of a BRAFV600E-specific TCR into T cells.

Main Results:

• The patient achieved a complete response to TIL therapy.
• Fewer than 30 nonsynonymous somatic mutations were identified, including the BRAFV600E oncogenic mutation.
• Rare CD4+ T cells specific for BRAFV600E and CD8+ T cells reactive to nonmutated self-antigens were found.
• T cell specificities expanded in blood post-therapy and persisted long-term.
• Gene-transferred TCR enabled CD4+ T cells to recognize BRAFV600E-expressing cells.

Conclusions:

• TIL therapy can be effective even in low-mutation-burden melanomas.
• BRAFV600E-specific CD4+ T cells are key mediators of antitumor response.
• TCR-engineered T cell therapy targeting BRAFV600E offers a potential treatment strategy for BRAF-mutated cancers.