Avaliação da resposta imune humoral ao longo do desenvolvimento de tumor de mama triplo-negativo

Abstract

Characterized by the absence of progesterone (PR), estrogen (ER), and human epidermal growth factor receptor 2 (HER2), triple-negative breast cancer (TNBC) is often associated with a worse prognosis, early disease recurrence, and a limited number of treatment options. Despite this, it is the subtype that exhibits the highest immune activity, with a presence of intense lymphocytic infiltration, which is associated with a better prognosis and higher treatment response rates. Although present, the impact of the development of triple-negative breast neoplasms on the dynamics of B lymphocytes, as well as the effect of emerging therapeutic modalities on this humoral immune response, is still poorly understood. Here, we report that the development of experimental breast tumors induced by 4T1 and E0771 cells resulted in an increase in B lymphocytes in the draining lymph node of animals in the early stages of carcinogenesis. While no significant differences were observed for regulatory B10 populations, we observed an increase in the number of LAG-3-expressing B lymphocytes, a phenotype with high expression of IgD, suggesting early stages of activation. This phenotype was also found in the transcriptome analysis using data from breast cancer patients, being verified in a portion of germinal center B cells, a population that, along with naive and memory B lymphocytes, was associated with a better progression-free survival (PFS) rate. Additionally, we demonstrated that although the combination treatment with anti-PD-1 + anti-LAG-3 reduced tumor volume and contributed to the increase of CD4 and CD8 T lymphocytes in the tumor microenvironment, no changes were observed for B lymphocytes after this treatment. Although the combination treatment led to a significant expansion of germinal center B cells and plasma cells in the draining lymph node of the animals, as well as an elevation of IgG1 in the serum, these antibodies were not able to better recognize tumor protein antigens. The results suggest that triple-negative tumors contribute to a diverse humoral immune response, characterized by high cellular diversity. Despite the detection of different phenotypes, functional assays are essential to determine the functions associated with each of these cells under pathological conditions and treatment.