Immunological tumor status may predict response to neoadjuvant chemotherapy and outcome after radical cystectomy in bladder cancer

Abstract

Bladder cancer (BC) is the ninth most common cancer worldwide. Radical cystectomy (RC) with neoadjuvant chemotherapy (NAC) is recommended for muscle-invasive BC. The challenge of the neoadjuvant approach relates to challenges in selection of patients to chemotherapy that are likely to respond to the treatment. To date, there are no validated molecular markers or baseline clinical characteristics to identify these patients. Different inflammatory markers, including tumor associated macrophages with their plastic pro-tumorigenic and anti-tumorigenic functions, have extensively been under interests as potential prognostic and predictive biomarkers in different cancer types. In this immunohistochemical study we evaluated the predictive roles of three immunological markers, CD68, MAC387, and CLEVER-1, in response to NAC and outcome of BC. 41% of the patients had a complete response (pT0N0) to NAC. Basic clinicopathological variables did not predict response to NAC. In contrast, MAC387+ cells and CLEVER-1+ macrophages associated with poor NAC response, while CLEVER-1+ vessels associated with more favourable response to NAC. Higher counts of CLEVER-1+ macrophages associated with poorer overall survival and CD68+ macrophages seem to have an independent prognostic value in BC patients treated with NAC. Our findings point out that CD68, MAC387, and CLEVER-1 may be useful prognostic and predictive markers in BC.

Prognostic Role of Survivin and Macrophage Infiltration Quantified on Protein and mRNA Level in Molecular Subtypes Determined by RT-qPCR of KRT5, KRT20, and ERBB2 in Muscle-Invasive Bladder Cancer Treated by Adjuvant Chemotherapy

“…Importantly, in our study, the proliferative subset of MIBC patients having better survival (i.e., 60% DSS after 5 years) could be further dissected by macrophage infiltration. Tervahartiala et al [ 14 ] found that MAC387+ cells as well as CLEVER-1+ macrophages and vessels are associated with the response after neoadjuvant chemotherapy in bladder cancer patients. High MAC387+ tumor cell density was associated with disease progression after neoadjuvant chemotherapy, whereas the majority of patients with a lower amount of MAC387+ tumor cells exhibited a complete response.…”

“…High MAC387+ tumor cell density was associated with disease progression after neoadjuvant chemotherapy, whereas the majority of patients with a lower amount of MAC387+ tumor cells exhibited a complete response. Patients with high amounts of CLEVER-1+ macrophages were associated with a poorer response to neoadjuvant chemotherapy, while higher amounts of CLEVER-1+ vessels were associated with a more favorable response [ 14 ]. The results of Tervahartiala et al [ 14 ] verified also their previous studies where they could demonstrate that CD68 and MAC387 are associated with poorer survival in bladder cancer patients, whereas CLEVER-1-positive vessels act more as a protective marker [ 32 ].…”

“…Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1, also known as stabilin-1 or STAB1) is a multifunctional immunosuppressive scavenger receptor expressed by lymphatic and vascular endothelial cells and tissue macrophages [ 13 ]. Its prognostic significance in bladder cancer is not clear, but there is evidence that high CLEVER-1-positive macrophage count associates with chemoresistance [ 14 ] in neoadjuvant-treated bladder cancer patients. The monoclonal antibody MAC387 detects an epitope on the calcium-binding protein MRP14/S100A9 present in the cytosol of monocytes and granulocytes [ 15 ].…”

Immunology, Immunotherapy, and Translating Basic Science into the Clinic for Bladder Cancer

“…The underlying reasons for these divergent findings are unclear, however in the second study, earlier stage tumors were evaluated (Ta-T2) as compared to tumors from more advanced disease (T1-T4) assessed in the first analysis. Additional studies of tumor macrophages and outcome in muscle invasive (MIBC) or nonmuscle invasive BCa (NMIBC) have measured cell surface proteins such as CD68 (all macrophages), MSC387 (recently infiltrated monocyte-derived macrophages), CD204 (M2-associated), CD163 (scavenger receptor), and CD169 (sialoadhesin), and in each case, tumor macrophages are associated with a negative patient prognosis [ 36–40 ]. Specifically in NMIBC, a long-term study of patients treated with BCG intravesical immunotherapy reported that recurrence free survival was worse for patients with tumor samples with “high” numbers of tumor-associated macrophages [ 41 ].…”

Detection of circulating tumor DNA for advanced bladder cancer: where are we going?

“…Several molecular biomarkers have been tested for prediction of response to NAC, including: regulators of apoptosis and cell survival ( 4 - 7 ), DNA repair genes ( 5 - 13 ), ERBB2 mutations ( 14 ) and gene expression signatures ( 15 - 17 ). Recently, immunological markers ( 18 ) and molecular subtypes of MIUC have been evaluated as potential biomarkers in patients treated with NAC ( 19 ).…”