Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival

Objective:Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies.Design:We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 patients with HIV-related diffuse large B-cell lymphoma (DLBCL) diagnosed in the era of combined antiretroviral therapy (1996-2007) at Kaiser Permanente California. Eighty patients with HIV-unrelated DLBCL were included for comparison.Methods:Data on patients' clinical history were obtained from Kaiser Permanente's electronic health records. The density of stromal CD4(+), CD8(+) and FOXP3(+) T cells and CD68(+) macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient's clinical history or tumor characteristics were examined using Kruskal-Wallis tests or Pearson's correlation coefficient. The effect of stromal immune infiltration on 2-year mortality was evaluated in multivariable logistic regression.Results:Compared with HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4(+) and FOXP3(+) T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4(+) cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not Epstein-Barr virus infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3(+) T cells. A higher density of infiltrating CD8(+) T cell was significantly associated with reduced mortality in patients with HIV-related DLBCL (odds ratio=0.30 [0.09-0.97] for 25 vs. <10%).Conclusion:These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.