Resposta imune e mecanismos de evasão na carcinogênese de lábio: um estudo imunoistoquímico

Abstract

Immune surveillance, mainly mediated by CD8 + T lymphocytes, recognize and destroy malignant or altered cells. However, through immunosuppressive strategies, such as the signaling pathways of the programmed cell death ligand-1 (PD-L1) and human leukocyte antigen-G (HLA-G), these mutated cells often escape the antitumor immune response. The aim of this study was to investigate and compare the immunoexpression of PD-L1, HLA-G, CD8 and granzyme B (GrB) in the microenvironment of lip squamous cell carcinomas (LSCCs; n = 40), actinic cheilitis (ACs; n = 55), and healthy lip mucosa (HLM; n = 10). The samples were submitted to immunohistochemistry and the analysis followed a semi-quantitative (PD-L1 and HLA-G) and quantitative methods (CD8 and GrB). Protein expression was compared between the three groups of samples, as well as with the lesion’s clinicopathologic parameters and overall survival of patients with LSCC. Correlation between proteins and the type of tumor microenvironment according to a presence of PD-L1 and CD8 were also evaluated. Statistical tests included Fisher's exact, Mann-Whitney, Kruskal-Wallis, Spearman's correlation, as well as the log-rank for comparison of the overall survival built through Kaplan-Meier method. Significance was set at p < 0.05. The CD8+ and GrB+ cell numbers progressively increased from HLMs to LSCCs, with ACs exhibiting intermediate numbers (p < 0.01). Lower expression of these proteins was associated with lymph node metastasis and poor tumor differentiation (p < 0.05). PD-L1 and HLA-G expression in neoplastic cells/keratinocytes and stroma/connective tissue was significantly higher in LSCCs and ACs, compared to HLMs (p < 0.05). PD-L1 was not significantly associated with clinicopathological aspects of the lesions. Most LSCCs showed coexistence of PD-L1+ and CD8+ cells (72.5%) in the tumor microenvironment. PDL1 was directly correlated to CD8+ and GrB+ lymphocytic infiltration in LSCCs (p < 0.05). Proteins expression was not associated with overall survival of LSCCs patients (p > 0.05). Our findings suggest that immunosuppressive molecules PD-L1 and HLA-G are consistently expressed from ACs and are maintained until advanced stages of LSCCs. The correlation between PD-L1 expression and the expression of CD8 and GrB in carcinomas suggests that that PD-L1 may appear as an escape mechanism against an active antitumor response.