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.


METHODS
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%).


CONCLUSIONS
These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.
aDepartment of Research and Evaluation, Kaiser Permanente Southern California, Pasadena bDivision of Research, Kaiser Permanente Northern California, Oakland cDepartments of Obstetrics and Gynecology and Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine at University of California Los Angeles dDepartment of Epidemiology, UCLA Fielding School of Public Health, Los Angeles eDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles fDepartment of Medicine and San Francisco General Hospital, University of California, San Francisco, San Francisco gLos Angeles Medical Center, Kaiser Permanente Southern California, Los Angeles, California, USA.
Chun
C
Chao
Lanfang
L
Xu
Michael J
MJ
Silverberg
Otoniel
O
Martínez-Maza
Lie-Hong
LH
Chen
Brandon
B
Castor
Donald I
DI
Abrams
Hongbin D
HD
Zha
Reina
R
Haque
Jonathan
J
Said
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002140:California; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051858:Forkhead Transcription Factors; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C418974:FOXP3 protein, human