Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer

Koti, M.; Ravenscroft, B.; Yolmo, P.; Chenard, S.; Rahimi, S.; Pace, K.; Sachdeva, K.; Jamaspishvilli, T.; Ghadei, H.; Garven, A.; Tyryshkin, K.; Berman, D. M.; Jackson, C.; Siemens, D. R.

doi:10.1101/2023.10.19.562817

bioRxiv · 10.1101/2023.10.19.562817

Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer

Koti, M.·Ravenscroft, B.·Yolmo, P.·Chenard, S.·Rahimi, S.·Pace, K.·Sachdeva, K.·Jamaspishvilli, T.·Ghadei, H.·Garven, A.·Tyryshkin, K.·Berman, D. M.·Jackson, C.·Siemens, D. R.

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Abstract

Non-muscle invasive bladder cancer (NMIBC) constitutes a significant clinical challenge, with over 50% of patients experiencing poor clinical outcomes in the form of early recurrence or progression following treatment with Bacillus Calmette-Guerin (BCG) immunotherapy. The pre-treatment tumor immune microenvironment (TIME) is an established determinant of response to BCG. This study explores the spatial profiles of CD79a+ B cells, CD163+ M2-like macrophages, proliferating and tissue-resident phenotypes of T cells, along with PD-1/PD-L1 checkpoint expression in pre-BCG treatment tumors of 173 patients (139 males, 34 females). Multiplex immunofluorescence staining of a tumor tissue microarray, revealed elevated infiltration of CD79a+ B cells, CD163+ M2-like macrophages, CD103+ cells, and CD8+ T cells at the tumor invasive margins. Increased epithelial PD-L1 immune-checkpoint expression in tumors was observed in female and male patients who exhibited significantly shorter recurrence-free survival (RFS). Importantly, high CD79a+ B cell density in BCG-treated females in both stromal and epithelial compartments exhibited significantly shorter RFS and progression-free survival compared to males. Stromal CD79a+ B cell density was positively correlated with M2-like macrophages, CD8+ T cells, CD103+ cells and PD-1 expressing cells. CD79a+ B cells, CD103+ cells, and M2-like macrophage density were associated with higher grade and enriched in basal subtype tumor. This study highlights the significance of an understudied role of B cells and their cellular neighborhoods in the pre-treatment TIME and BCG-therapy response. Overall, findings from this study underscore the importance of considering sex-related immunobiological differences in the stromal compartments of bladder tumors towards the development of optimal therapeutic targeting strategies.

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Koti, M., Ravenscroft, B., Yolmo, P., Chenard, S., Rahimi, S., Pace, K., Sachdeva, K., Jamaspishvilli, T., Ghadei, H., Garven, A., Tyryshkin, K., Berman, D. M., Jackson, C., Siemens, D. R.. 2023-10-20. Increased stromal densities of B cells, CD103+ cells, and CD163+ M2-like macrophages associate with poor clinical outcomes in BCG treated non-muscle invasive bladder cancer. https://doi.org/10.1101/2023.10.19.562817

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