Prognostic value of tissue-infiltrating immune cells in tumor microenvironment of follicular lymphoma: A meta-analysis.

Abstract Background The follicular lymphoma (FL) microenvironment is composed of follicular dendritic cells (FDCs), tumor-infiltrating CD4/CD8+ T cells (TILs), follicular regulatory T (Treg) cells, lymphoma-associated macrophages (LAMs), and immune checkpoint–related immune cells, all of which are relevant in the prognosis of FL, but their results remain controversial. Therefore, we performed this systematic review to explore the relationship between the FL microenvironment and prognosis. Methods Relevant studies were identified from PubMed, EMBASE and the Cochrane Library. Twenty-three trials involving 3336 patients with FL were included for analysis. Results This meta-analysis confirmed the unfavorable prognostic role of high CD21+/CD23+ FDC density in overall survival (OS) and progression-free survival (PFS). CD8+ or granzyme B+ TILs instead of CD4+ TILs are indicators for good OS. FoxP3+ Treg cells was not associated with prognosis, and even in subgroup analysis neither the number of cells nor the infiltration pattern had predictive value. A high degree of CD68+ macrophage infiltration was a negative prognostic factor for OS, but was associated with good prognosis in the rituximab-era subgroup. Although there was no correlation between PD1-positive immune cells and prognosis, subtypes with the follicular helper T (TFH) or exhausted T cell (TEX) phenotype tended to influence prognosis. The HR in the short time to transformation (TTT) analyses suggested that high CD68+ LAM numbers, diffuse pattern of FOXP3+ Treg cells and PD1+ cells, and high PD-L1 cell numbers are adverse factors leading to early transformation. Conclusions Multiple tissue-infiltrating immune cells in microenvironment play critical and different roles in FL prognosis.