Dados do Trabalho

Título

Impact of Tumor Microenvironment Interactions with HABP4 and SERBP1 Proteins on Bladder Cancer Progression

Resumo

This study characterized and compared the immunohistochemical signatures associated with the cytotoxic inflammatory response (IFN-γ, CX3CR1+CD8+ T cells, iNOS+ M1 macrophages), immune checkpoints (PD-L1, CTLA-4), and the presence of immunosuppressive cells [CD163+M2 macrophages, Foxp3+regulatory T (Treg) cells] within bladder cancer (BC) samples. Furthermore, it aimed to correlate these immune signatures with the functional dynamics of Hyaluronic Acid Binding Protein 4 (HABP4) and Serpin mRNA Binding Protein 1 (SERBP1). A total of 30 formalin-fixed, paraffin-embedded bladder samples were obtained from patients diagnosed with BC at Municipal Hospital of Paulínia, Brazil. The samples were divided into three groups (n = 10 samples per group): Group 1 - Initial Non-Muscle Invasive Bladder Cancer (NMIBC); Group 2 - BCG-unresponsive NMIBC; and Group 3 - Muscle Invasive Bladder Cancer. Subsequently, the samples were submitted to immunohistochemical analyses. The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Our results demonstrated that total immunoreactivities for IFN-γ, iNOS and CX3CR1 were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. CTLA-4 and PD-L1 immunoreactivities were significantly higher (p < 0.01) in Group 1 compared to Groups 2 and 3. Conversely, immunoreactivities for CD163 and Foxp3 were significantly higher (p < 0.01) in Groups 2 and 3 compared to Group 1. This study marks the first elucidation of HABP4 and SERBP1 immunoreactivities in the context of BC. We observed that immunoreactivity for SERBP1 was significantly higher (p < 0.01) in Groups 2 and 3 than in Group 1, implicating its overexpression in the facilitation of tumor progression. In a contrasting manner, HABP4 demonstrated significantly greater immunoreactivity in Group 1 compared to Groups 2 and 3, indicating a potential inhibitory effect on cellular proliferation. Conclusions: The augmented presence of Foxp3+Treg cells and CD163+M2 macrophages, concomitant with SERBP1 overexpression and the decrease of immune checkpoints, likely compromises the therapeutic efficacy of BCG. This immunosuppressive milieu hinders the activation, proliferation, and effector functions of CD8+ T cells, thereby promoting tumor progression. Conversely, a heightened infiltration of CX3CR1+CD8+ T cells and iNOS+M1 macrophages promotes a cytotoxic microenvironment, rendering it more amenable to immunotherapeutic interventions.

Palavras Chave

Bladder cancer; HABP4; SERBP1