Dados do Resumo

Título

T-CELL RECEPTOR DIVERSITY AND IMMUNE CONTEXTURE: A PROGNOSTIC INDICATOR IN BLADDER CANCER

Introdução

Bladder cancer can be classified as non-muscle-invasive (NMIBC) and invasive (MIBC). Immune Checkpoint Inhibitor (ICI) therapies have shown effectiveness in managing both types of bladder cancer, highlighting the critical role of the immune system in controlling tumor growth. The T-cell receptor (TCR) repertoire in cancer patients can help better understand antitumor responses and has been suggested to have predictive and/or prognostic value, both for the disease and in response to treatments.

Objetivo

We believe that TCR diversity and the presence of CD8+ and CD3 cells in the tumor microenvironment, as measured by the Immunoscore Biopsy-adapted Expression-based (ISBE) may serve as significant biomarkers for predicting treatment response in bladder cancer patients.

Métodos

To evaluate this, we analyzed three distinct cohorts: (1) BCG, which involved computational analysis of TCR-seq data from tumor-infiltrating lymphocytes (TILs) in 23 NMIBC patients who had TURBT followed by BCG treatment; (2) BUT, encompassing Blood, Urine, and Tumor samples from 6 NMIBC/MIBC patients who also underwent TURBT; (3) ABACUS, including 88 MIBC patients treated with ICIs before cystectomy. We performed TCR sequencing on DNA from tumor FFPE, total PBMCs, PBMC-derived CD8+ cells, and urine for the BCG and BUT cohorts. For the ABACUS cohort, we used the publicly available transcriptomic data to determine the ISBE score.

Resultados

For the BCG cohort, no significant correlation was found between TCR diversity and treatment response (medians of 7.34 and 6.3, respectively), nor with extended recurrence-free survival (p=0.4, Log-rank test). The similarity of the TCR repertoire among additional FFPE tumors, PBMCs, CD8+ cells, and urinary DNA was also assessed. After accessing ISBE for 84 patients in the ABACUS cohort, we did not observe a significant association between pathological complete response (pCR) and ISBE (p=0.52; Fisher’s Test), although we noted a lower representation of high ISBE patients who did not respond to treatment. Additionally, we found a significant association between ISBE and CD8+ immune phenotypes (p=0.01, Fisher's Test) in the post-treatment group, indicating that patients with higher ISBE levels had a greater presence of inflamed immune cells. These results are consistent with existing literature, showing that increased CD8+ cell infiltration is associated with pCR in MIBC patients.

Conclusões

Despite the limited number of urine samples, the results showed higher TCR similarity between urine and TILs compared to PBMCs. This supports the literature suggesting urine as a viable DNA source for biomarker analysis. We plan to expand the study to validate urine as a potential source of T cells for biomarker quantification. The study was approved by the HSL Research Ethics Committee (CEP, opinion no. 3.853.540).

Financiador do resumo

CAPES 88887.699446/2022-00

Palavras Chave

Bladder cancer; T-cell receptors and TCR diversity