Análise de alterações imunológicas sistêmicas e locais em pacientes com câncer de penis

Abstract

Penile cancer (CaPe) is a rare malignancy with limited therapy for the disease with more aggressive characteristics. Therapies based on the immune system are modalities that have shown great effectiveness in various stages of carcinomas. With the aim of allowing a comprehensive characterization of the antitumor response of patients with CaPe, we evaluated the immunological profile and functionality of dendritic cells derived from monocytes from these patients. For this, peripheral blood samples were collected for the generation of monocyte-derived dendritic cells (mo-DCs), for lymphocyte immunophenotyping analysis, apoptosis and proliferation assay; and tumor tissues were used for cytokine detection and phenotyping of immune cells infiltrating the tumor. Clinical and histopathological data were obtained from 35 patients with CaPe. Mo-DCs obtained from the peripheral blood of 19 healthy donors were used as controls. Plasma cytokine analysis showed no difference between case and control groups, however, IL-6 and IL-4 levels were 3x and 4x, respectively, higher in patients than in healthy donors. The frequency of lymphocyte subpopulations was not different between donors and patients, however the CD4+/CD8+ ratio was higher (p=0.0143) in patients. Patient has lower expression of the costimulatory molecule CD86 (p=0.0004). Furthermore, the allostimulatory capacity of healthy lymphocytes (p=0.0456) was lower for the patients' mo-DCs. Moreover, co-culture of mo-DC from patients with allogeneic lymphocytes from healthy donors showed IL-17 production (p=0.0262). In the apoptosis assay of lymphocytes cultured with tumor supernatant, lymphocytes from patients with CaPe showed less death level compared to healthy lymphocytes. In the profile of immune cells infiltrating in the tumor, the data showed a higher frequency of CD3+ T cells (7.99%) and even high expression of PDL-1 (p=0.0010). Finally, the data showed a significant clinical correlation between tumor staging and cell surface expression of CD86 (r2=0.5751, p=0.0349) and PD-L1 (r2=0.7220, p, 00092) on mo-DCs. The results suggest that patients with penile carcinoma have an immunosuppressive profile, opening perspectives for a better understanding of the tumor microenvironment and the potential to restore or immunomodulate components used in antitumor immunotherapy.