Contraction of T cell richness in lung cancer brain metastases

Area of Science:

• Immunology
• Oncology
• Genetics

Background:

• Adaptive immune responses to tumor heterogeneity and clonal evolution in non-small cell lung cancer (NSCLC) are poorly understood.
• Tumor mutation burden and neoantigen prediction are key factors in cancer progression and treatment response.

Purpose of the Study:

• To investigate T cell receptor (TCR) repertoire diversity and clonal evolution in NSCLC primary lesions and paired brain metastases.
• To correlate immune cell profiles with tumor mutational landscape in different metastatic sites.

Main Methods:

• Profiling of T-cell receptor β complementarity determining region 3 (TCRβ CDR3) sequences from 20 NSCLC patients.
• Analysis of T cell clone richness, abundance, and overlap between primary tumors and matched brain metastases.
• Assessment of tumor mutation burden and predicted neoantigens in paired lesions.

Main Results:

• A significant reduction in unique T cell clones was observed in brain metastases compared to primary NSCLC lesions.
• Minimal overlap of T cell clones was found between paired primary and metastatic lesions, indicating lesion-specific immune responses.
• Brain metastases exhibited higher non-synonymous mutation burdens than primary tumors, despite the decreased T cell clone richness.

Conclusions:

• Primary NSCLC tumors harbor greater T cell clone richness than their paired brain metastases, even with higher metastatic mutation burden.
• These findings suggest distinct immune microenvironments in primary versus metastatic lung cancer.
• The observed immune landscape differences may inform the development of targeted immunotherapies for NSCLC brain metastases.