197P - Comprehensive immunoprofiling of the intratumoral and peripheral T cell receptor gene repertoire in triple-negative breast cancer patients

Background

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with not fully elucidated pathobiology and a lack of available prognostic biomarkers. The T cell receptor (TR) gene repertoire is a robust prognostic and predictive biomarker in other cancers yet has not been extensively studied in TNBC. Here, we characterized the immunogenetic features of intratumoral (iTR) and peripheral (pTR) TR gene repertoires using next-generation sequencing (NGS).

Methods

NGS-based TR gene repertoire analysis was performed in paired DNA samples from tumor-derived and peripheral blood T cells in 43 TNBC cases at diagnosis. Repertoire diversity was assessed by Shannon Index (SI). Patients were grouped into age categories based on the average menopausal age of 51 years to explore potential age-related immunogenetic differences. Pearson’s coefficient (r) was employed to analyze correlations between TR diversity and clonality, age at diagnosis, and disease stage.

Results

The iTR and pTR gene repertoires were distinct, with minimal or no overlap. Both the iTR and pTR repertoires exhibited oligoclonality, however this was significantly higher in the former (Md SI: 5.1 vs 7, p<0.0001). Clonotypes in the iTR repertoire utilized predominantly the TRBV12-3, TRBV19 and TRBV29-1 genes, whereas TRBV6-5 prevailed in the pTR repertoire. Cox regression models revealed significantly worse overall survival (OS) and progression-free survival (PFS) (HR>2, p<0.01) in patients with iTR clonotypes encoded by TRBV11-3 and TRBV15. TRBV2, TRBV7-9 and TRBV10-2 usage was associated with shorter OS and PFS in the pTR repertoire (HR>2, p<0.01). Lower pTR diversity correlated with more advanced disease stages (r=-0.31, p<0.04), mainly in older patients (r=-0.5, p<0.01).

Conclusions

Distinct immunogenetic profiles between iTR and pTR repertoires in TNBC likely stem from the distinct microenvironmental dynamics in each compartment. Skewing of the repertoire and correlation of OS and PFS with specific immunogenetic signatures may reflect the activation of anti-tumor T-cell responses, potentially intensifying in response to neoantigens produced by age-related and tumor-stage accumulation of mutations.

Legal entity responsible for the study

Antonios Mingos.

Funding

Has not received any funding.

Disclosure

G. Fountzilas: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Stocks/Shares: Genprex, Daiichi Sankyo, Rafael Holdings, Formycon; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Novartis. All other authors have declared no conflicts of interest.