Can T-cell receptor diversity and immune contexture predict bladder cancer outcomes?

Keywords

bladder cancer - T-cell receptors - TCR diversity

Bladder cancer is a clinically heterogeneous disease stratified into non-muscle-invasive (NMIBC) and invasive (MIBC). In addition to transurethral bladder tumor resection (TURBT) or radical cystectomy, immunotherapy is a treatment option for both cancer types, uncovering the immune system's role in tumor control. We hypothesize that levels of CD8+ and CD3 T-cells infiltrating the tumor (TIL), measured through an adaptation of the Immunoscore for expression data (IS), and T-cell receptor diversity (dTCR), characterized through TCRseq, are potential predictive and prognostic biomarkers. We herein evaluated 3 cohorts: (1) BCG (TIL samples from 23 NMIBC patients who underwent TURBT + adjuvant BCG); (2) BUT (blood, urine, and tumors samples from 6 NMIBC/MIBC patients who underwent TURBT), and (3) ABACUS (84 MIBC patients that underwent neoadjuvant Atezolizumab + cistectomy). We performed TCRseq for (1) and (2) cohorts using DNA from tumor-FFPE (TIL), PBMC, PBMC-derived CD8+, and urine. For cohort (1), we did observe a significant difference in dTCR between BCG responders (n = 9) vs. non-responders (n = 14, T-test, p = 0.35), nor longer recurrence-free survivals in high dTCR (p = 0.4, Log-rank test). Just for the small BUT cohort we compared the TCR repertoire similarity of TIL vs. PBMC, CD8+, or urine. We observed a higher similarity between urine and TIL (0.0225, Jaccard index) than PBMC or CD8+ vs. TIL (<0.0025). Under authorized access from the ABACUS study, we used primary tumors’ RNAseq data plus CIBERSORTx to calculate IS (low n = 5, intermediate n = 59, or high n = 20) and correlate with pathological complete response (pCR). We did not observe a significant association between pCR and ISE (p = 0.52; Fisher's Test), but non-responders were depleted from high ISs. Our preliminary results find support on the literature: (i) the greater the CD8+ infiltration, the more pCR in MIBC cases. (ii) TCR repertoire from urine is a proxy for the tumor microenvironment. We are currently recruiting more patients to increase our BUT cohort to validate dTCR from urine as a potential biomarker.

Corresponding author: Stefani de Moura Souza (e-mail: [e-mail]).