The tumor microenvironment plays a vital role in cancer development [1,2]. The interaction between tumor cells and stromal cells, such as infiltrating immune cells, fibroblasts and endothelial cells may create a local environment that supports or inhibits tumor growth. Antitumor immunity mediated by infiltrating T cells, macrophages and dendritic cells play an important role in determining disease progression and patient outcome in a variety of cancers, including diffuse large B-cell lymphomas (DLBCLs) [3–5]. To this end, several studies have demonstrated the prognostic significance of the stromal immune cells through gene expression profiling [6–8], immunohistochemistry [9–11] or functional/animal studies [12,13], lending support to therapeutic strategies that aim to restore immune surveillance in the tumor microenvironment.
Despite knowledge advancements about antitumor immunity and its treatment implications in lymphomas in the general population, there is a lack of studies examining the microenvironment for HIV-related lymphomas. As such, little is known about the microenvironment and the role of antitumor immunity among immunodeficient populations, such as HIV-infected patients. Liapis et al. have for the first time attempted to characterize the microenvironment of HIV-related DLBCL. They showed increased vessel density and altered infiltrating T-cell populations compared with patients with sporadic DLBCL. These findings highlighted the need to better understand tumor microenvironment unique to HIV-related lymphomas and its therapeutic implications.
In this study, we examined the immune component of the microenvironment, including stromal T-cell subpopulations and tumor-associated macrophages in HIV-related DLBCL. We sought to understand whether the composition of infiltrating immune cells differs by clinical and molecular characteristics of the tumor, whether the composition of infiltrating immune cells may be affected by HIV disease history such as severe immunosuppression, and whether the density of specific infiltrating immune cells can predict patient survival in HIV-related DLBCL. To warrant generalizability to current clinical management of DLBCL in HIV-infected patients, the present study is entirely based on contemporary patients diagnosed in the postcombination antiretroviral therapy (ART) era.
All adult HIV-infected patients (≥18 years) diagnosed with incident DLBCL between 1996 and 2007 were identified from the Kaiser Permanente Southern and Northern California Health Plans, two large integrated healthcare delivery systems. DLBCL diagnoses were ascertained from Kaiser Permanente's Surveillance, Epidemiology and End Results-affiliated cancer registries. HIV infection status was identified through record linkage with the health plans’ HIV registries.
A group of patients with HIV-unrelated DLBCL were also selected for comparison. Tumor biology can differ by age and DLBCL tend to be diagnosed at younger age in HIV-infected persons. Furthermore, the HIV-infected cohort in California was 95% men and the majority was of non-Hispanic White race. To ensure comparability of patients with HIV-unrelated DLBCL with the patients with HIV-related DLBCL, we matched patients 1 : 1 by age groups (i.e., <30, 30–50 and >50 years), sex and race (White vs. non-White). Appropriate tumor specimens of matched HIV-unrelated DLBCL patients for patients with HIV-related DLBCL were unavailable. The comparisons for those four patients with HIV-infected DLBCL were thus replaced by additional matched HIV-unrelated DLBCL patients for other HIV-infected patients.
Pathology review and tissue microarray construction
Archived tumor specimens were retrieved and hematoxylin and eosin-stained slides were reviewed to confirm the DLBCL diagnosis as well as to identify representative tumor blocks for tissue microarray (TMA) construction (at the UCLA Core Microarray Facility). Whenever possible three 0.6-mm cores from different areas of the donor block were obtained from each case and inserted in a grid pattern into a recipient paraffin block using a tissue arrayer (Beecher Instruments, Silver Spring, Maryland, USA).
Immunohistochemistry staining was performed on TMA cores to analyze the stromal expression of CD4+ (helper T cells), CD8+ (cytotoxic T cells), FOXP3+ (Treg cells), and CD68+ (macrophage). In addition, the expression of the following markers was assessed in the tumor cells: BCL2, BCL6, p53, Ki-67, cMYC. Expression of CD10+, MUM1 and BCL6 were used to determine the germinal center phenotype using the Hans’ algorithm . The percentage of stromal cells that expressed CD4+, CD8+, FOXP3+ and CD68+, and the percentage of tumor cells that expressed Ki-67 were digitally scored on a computerized automated platform. The percentage of tumor cells that expressed BCL2, BCL6, p53 and cMYC was scored manually by one study pathologist and confirmed by another. Cases with discrepant scores (about 10%) were resolved by re-review with double-headed microscope. Tumor Epstein–Barr virus (EBV) infection was determined by in-situ hybridization of EBV encoded RNA and was considered positive if at least 75% of the DLBCL cells had detectable EBV. Among EBV-positive tumors, LMP1 expression was determined based on immunohistochemistry staining.
Normal tonsillar lymphoid tissue was included as a positive control. Negative controls for each case consisted of substituting the primary antibody with isotype-specific noncross reacting antibody matching the primary antibody. The detailed information on TMA construction, antibody, incubation method and signal detection for each marker were described elsewhere .
Diffuse large B-cell lymphoma morphologic variants
DLBCL morphologic variant subtyping was performed by the two study pathologists (J.S. and H.D.Z.), who independently reviewed pathology reports, hematoxylin and eosin slides and stained tumor marker expression data. Minor classification discrepancies on two patients were resolved by the pathologists after applying the WHO's 2008 classification system of tumors of the hematopoietic and lymphoid tissues.
Ascertainment of patient survival
Two-year mortality was chosen as the outcome because most deaths in HIV-infected patients (85% in our study) occurred within 2 years after DLBCL diagnosis. Overall mortality ascertainment was complete for all patients (even if the person terminated Kaiser Permanente membership) through record linkage with Kaiser Permanente's membership and utilization files, California's state death file and Social Security death records. As such, there was no loss-to-follow-up.
The International Prognostic Index (IPI) was calculated based on age, clinical stage, extranodal involvement, serum lactose dehydrogenase, and performance status [17,18]. Age at DLBCL diagnosis, stage at diagnosis, extranodal involvement and initial chemotherapy were collected from Kaiser Permanente's cancer registries. Serum lactose dehydrogenase level and circulating CD4+ cell counts at DLBCL diagnosis (and their nadir) were obtained from the laboratory databases. Performance status and chemotherapy were ascertained from standardized medical record review . We collected HIV disease factors from HIV registries, including prior AIDS diagnosis, use of ART and duration of known HIV infection.
The density of the five stromal immune cells were calculated and compared by HIV status using the t-test statistic. Next, among HIV-infected patients, we compared the density of the stromal immune cells by stage at diagnosis, DLBCL variant (centroblastic, immunoblastic and plasmablastic), germinal center phenotype, prior AIDS diagnosis, ART use prior to DLBCL diagnosis and tumor EBV infection and LMP1 status, using the Kruskal–Wallis tests. The association between circulating CD4+ cell count (both at DLBCL diagnosis and nadir) and infiltrating immune cells was examined using Pearson's correlation coefficient. Similarly, the association between infiltrating immune cells and tumor molecular characteristics, including the expression of BCL2, BCL6, p53, Ki-67 and cMYC, was examined using Pearson's correlation coefficient.
Kaplan–Meier survival curves were generated for CD8+ and FOXP3+ T cells and CD68+ macrophage for the following density categories: less than 10, 10–24, 25–49, 50–74 and at least 75%. However, because less than five patients had stromal immune cell density at 50% or greater, the following combined categories were presented: less than 10, 10–24 and at least 25%. Because most patients with HIV-related DLBCL had minimal CD4+ T-cell infiltration, we dichotomized CD4+ T cells into two categories: less than 1 and at least 1%. The association between infiltrating immune cells and 2-year overall mortality was examined using bivariate and multivariable logistic regression adjusting for IPI, germinal center phenotype and DLBCL variant. Multivariable models restricted to those who received chemotherapy treatment were also performed. Missing data were handled using the multiple imputation method described by Rubin . All analyses were performed with SAS Version 9.2 (SAS Institute, Cary, North Carolina, USA).
The demographic and clinical characteristics of the 80 patients with HIV-related and the 80 with matched HIV-unrelated DLBCL are presented in Table 1. The mean age at DLBCL diagnosis was similar by HIV status (50 years old) due to matching. Compared with HIV-uninfected patients, HIV-infected patients were more likely to be diagnosed at advanced stage (48 and 29%; P = 0.01), with extranodal involvement (43 vs. 11%, P < 0.01), germinal center phenotype (39 vs. 26%; P = 0.01), and immunoblastic (23 vs. 6%) or plasmablastic subtypes (8 vs. 1%, P < 0.01). HIV-infected patients in this study had a mean circulating CD4+ cell count at DLBCL diagnosis of 206 cells/mm3, and a mean of 5 years duration of known HIV infection prior to DLBCL diagnosis. In addition, 43% of the patients with HIV-infected DLBCL had a prior AIDS diagnosis, and 65% patients had a history of ART use at time of DLBCL diagnosis (Table 1).
HIV infection status and stromal immune cells
Density of infiltrating immune cells by HIV infection status is shown in Table 2. The majority of HIV-related DLBCL patients had minimal CD4+ T-cell infiltration (i.e., 75% of the patients had less than 1% of stromal CD4+ T cells, data not shown). Compared with HIV-unrelated DLBCL, HIV-related DLBCL showed significantly reduced density of infiltrating CD4+ T cells (mean = 1.8 vs. 14.8% for HIV-related vs. HIV-unrelated DLBCL, respectively, P < 0.001) and FOXP3+ Treg cells (7.3 vs. 22.5%, P < 0.001), but significantly increased density of infiltrating CD8+ T cells (19.9 vs. 14.6%, P = 0.017) and macrophages (15.0 vs. 8.7%, P = 0.006).
Stromal immune cells and HIV disease history
There was a greater degree of stromal macrophage infiltration in those with lower CD4+ cell count at DLBCL diagnosis (Pearson's correlation coefficient = −0.25, P value = 0.05). A similar but weaker association with stromal macrophages and the nadir circulating CD4+ cell count was also observed (Pearson's correlation coefficient = −0.18, P value = 0.14). No association was found between circulating CD4+ T cells and stromal density of any of the T cells examined (data not shown). However, having an AIDS diagnosis prior to the DLBCL diagnosis was associated with a substantially reduced infiltrating CD4+ T cells (mean [SD] = 0.6 [6.91%] and 2.7% [0.9%], P value = 0.09). Although all our patients with HIV-related DLBCL were diagnosed in the ART era, not all patients had initiated ART at the time of DLBCL diagnosis. To this end, we did not find an association between ART use prior to DLBCL diagnosis and any of the stromal immune cells examined (data not shown).
Epstein–Barr virus infection status and stromal immune cells in HIV-related diffuse large B-cell lymphoma
Seventy patients with HIV-related DLBCL who had a valid EBV results were included in this analysis. One-third (22 of 70) of them were positive for tumor EBV infection. When we examined the stromal immune cells by EBV status, a greater density of CD4+ T cells was found in the EBV-negative compared with the EBV-positive DLBCLs (mean: 2.2 vs. 0.5%, respectively), although this difference was not statistically significant (P = 0.19). EBV-negative HIV-related DLBCL also demonstrated slightly lower density of FOXP3+ Treg cells compared with EBV-positive DLBCL (mean: 6.2 vs. 9.6%, respectively, P = 0.07). The level of stromal CD8+ T cell (20.6 vs. 19.8%) and CD68+ macrophages (13.4 vs. 15.9%) appeared to be similar by tumor EBV status. When we explored the link between LMP1 expression and these stromal immune cells among EBV-positive HIV-related DLBCLs, no association was found between LMP1 expression and CD4+ or FOXP3+ T cells (data not shown).
Stromal immune cells and diffuse large B-cell lymphoma characteristics
When we examined the stromal immune cells by DLBCL variant in HIV-related DLBCL, we observed a significantly elevated density of stromal FOXP3+ Treg cells in plasmablastic subtype, compared with centroblastic or immunoblastic subtypes (mean [SD] = 13.4 (9.1%), 6.5 (9.2%), and 7.7% (10.6%), respectively, P = 0.04). Stromal macrophage density appeared to be elevated in immunoblastic subtype compared with the centroblastic subtype despite lack of statistical significance (mean [SD] = 24.2 (21.3%) and 11.8% (12.0%), respectively). No clear association was found between the stromal immune cells examined and clinical stage or cell-of-origin (data not shown).
When we examined the relationship between stromal immune cells and tumor molecular characteristics, stromal FOXP3+ Treg cells were found to be positively associated with tumor expression of p53 and cMYC (Pearson's correlation coefficient = 0.37 [P < 0.01] and 0.32 [P < 0.1], respectively], and inversely associated with BCL6 (Pearson's correlation coefficient = −0.31 [P = 0.01]) (Table 3).
Stromal immune cells and patient survival
Figure 1 shows the Kaplan–Meier survival curve in HIV-related DLBCL by stromal immune cell density. In multivariable logistic regression adjusting for IPI, germinal center phenotype and DLBCL variant, a higher density of stromal CD8+ T cells was significantly associated with reduced mortality (odds ratio [OR] for ≥25 vs. <10% = 0.30, 95% confidence interval 0.09–0.97). Reduced mortality was also suggested for those with higher density of stromal CD4+ T cells (OR for >1 vs. ≤1% = 0.43 [0.14–1.31]), and those with lower density of stromal macrophages (OR for >25 vs. <10% = 2.14 [0.48–9.43]), despite lack of statistical significance (Table 4). Similar OR estimates were obtained when we restricted the analyses to only those who received chemotherapy (data not shown).
Little is known about the tumor microenvironment in the setting of HIV-related lymphomas. In this study, we found significant differences in the density of important stromal immune cells between HIV-related and HIV-unrelated DLBCL, confirming findings previously reported by Liapis et al. based on a smaller sample. In addition, we observed an association between stromal immune cells and HIV disease history, a novel finding that may have implication for HIV disease management. Most importantly, we are among the first to link the density of stromal immune cells to patient survival outcomes in HIV-related DLBCL and reported the prognostic significance of CD8+ T cells on survival. These findings suggest that novel therapeutic approaches targeting the microenvironment, for example, by restoring T-cell mediated tumor surveillance may have particular benefits among HIV-infected patients who do not respond well to standard chemotherapy.
The reduced density of Treg cells and elevated infiltration of macrophages seen in HIV-related DLBCL is consistent with a pattern generally associated with poorer prognosis. Intratumoral T cells are thought to have an important impact on antitumor immunity . Treg cells affect immune responses of a variety of immune cells, including T cells, B cells and natural killer cells . Although Treg cells are thought to induce immunosuppressive phenotype, several studies of DLBCL and follicular lymphoma have linked high number of Treg cells to superior survival [23–25]. Tumor-associated macrophages, on the contrary, have generally been shown to correlate with disease progression in a variety of cancers, including DLBCL and follicular lymphomas [26,27]. As shown in in-vitro and in-vivo studies, macrophages may promote angiogenesis by secreting cytokines and other angiogenic factors such as the VEGFA and MMP9, which also support the growth of lymphomas . We also observed very limited infiltrating CD4+ T-cell population in HIV-related DLBCL. The prognostic significance of infiltrating CD4+ T cells is less clear and may depend on the distribution of subpopulations of CD4+ T cells. However, some studies suggest favorable survival profiles for patients with higher number of overall stromal CD4+ T cells [29,30].
Interestingly, patients with HIV-related DLBCL did not have reduced level of stromal CD8+ T cells in our study. Studies suggest that CD8+ T cells may directly target lymphoma cells . Higher stromal density of CD8+ T cells significantly predicted improved patient survival in our cohort of HIV-related DLBCL, independent of the IPI score. Our finding is consistent with those in lymphomas in the general population [32–34]. The relationship between stromal CD8+ T cells and patient survival outcomes may reflect compromised major histocompatibility complex restricted immune function, resulting in a loss of effective tumor immunosurveillance . Loss of cell adhesion molecules in the microenvironment has also been linked to loss of stromal CD8+ T- cell function, when loss of stromal CD8+ T-cell function has been linked to poor patient outcomes . Our findings suggest that CD8+ T cells may be an important component of lymphoma-specific immune response in HIV-related lymphomas. These stromal immune cells may also serve as useful markers for patient risk stratification beyond the traditional clinical IPI algorithm.
An additional novel contribution of this study is the preliminary evidence that host immune history may play a role in shaping the tumor microenvironment. We showed that patients with prior AIDS-defining conditions, primarily opportunistic infections, and low circulating CD4+ cell count at DLBCL diagnosis tended to have reduced density of stromal CD4+ T cells and increased macrophage infiltration, respectively. Several previous studies, including our own work, have shown that circulating CD4+ cell count and/or prior AIDS are independent prognostic predictors in patients with HIV-related lymphoma [36,37]. Our data suggest that one of the potential mechanisms of the prognostic impact of these HIV disease factors may be though modifying the tumor microenvironment. If this is confirmed, then the importance of maintaining circulating CD4+ cell count would not only be relevant to preventing the development of HIV-related lymphomas, but also would promote a better prognosis in those who develop such malignancies.
EBV infection of tumor cells is seen in about one-third of the contemporary HIV-related DLBCL cases. Recent data suggest that EBV-mediated pathogenesis involved interaction with the tumor microenvironment . Thus, we hypothesized that EBV-positive DLBCLs recruited a particular subset of immune cells. However, contrary to our hypothesis, no clear pattern of stromal immune cells was seen in DLBCLs positive for EBV infection. Although a statistically significant difference was found for Treg cells, the degree of the difference appears unlikely to be clinically meaningful. LMP1 expression was not associated with stromal CD4+ T cells or Treg cells. However, only 22 patients with EBV-positive DLBCL were included in this comparison; thus, the LMP1 analysis should be considered exploratory. A previous study that examined the presence of EBV infection in pediatric patients with DLBCL also found no alteration of the T-cell subsets in EBV-positive tumors . However, these results do not exclude the possibility that the presence of EBV may adversely affect the function of these T cells. In fact, studies suggest that EBV may impair the function of cytotoxic T cells and contribute to decreased immune surveillance .
Our results provide some evidence for the bidirectional interactions between the tumor and the microenvironment, as we observed significant correlations between certain molecular tumor characteristics and stromal immune cells. We examined the expression of five oncogenic proteins that are known to play a central role in lymphoma development and progression; three of these are correlated with the stromal density of Treg cells. We also observed a positive association between p53 expression and infiltrating CD4+ T cells population. It has been proposed that functional p53 protein is involved in the induction of antitumor CD4+ T-cell response via expression of major histocompatibility complex class-II antigens, and the absence of p53 may reduce the induction of CD4+ T-cell activity . Another potential explanation to the association we observed might be that the p53 peptides presented to immune cells may serve as a potential mechanism for triggering antitumor immune response . It is also possible that some of the correlations we observed simply reflected certain microenvironment characteristics that simultaneously promote/inhibit biologic processes in both the tumor and the stromal. For example, proinflammatory cytokines such as interleukin-6 and tumor necrosis factor-α have been shown to trigger the expression of BCL6 in multiple myeloma cells . Interleukin-6 is known to be a negative regulator for Treg cells . It is thus possible that the inverse association observed between tumor BCL6 expression and infiltrating Treg cells may be due to a proinflammatory cytokine environment. Our study, however, was not designed to address if it is the specific tumor characteristics that recruit (or through de-novo generation) the Treg cells, or whether the specific stromal immunity that induces or promotes the expression of certain oncogenic proteins, or both. To date, knowledge on the biologic processes that underlie the interplay between tumor and its microenvironment remains limited. Additional laboratory and clinical studies are needed to further elucidate the interaction between tumor, tissue and system level factors.
A potential limitation of this study was the limited sample size for certain subgroup comparisons. This limitation in sample size may also explain the lack of statistical significance between the density of stromal Treg cells and macrophages with survival outcomes. However, our study is based on a well defined cohort of patients with HIV-related DLBCL from the ART era that is among the largest reported in the literature. Another limitation is that we did not distinguish the subpopulations of stromal CD4+ T cells and tumor-associated macrophages, and we did not measure cytokine production or other factors that may affect immune cell functions.
In conclusion, we found that the composition of stromal immune cells in HIV-related DLBCL was significantly different from that found in HIV-unrelated DLBCL, and were consistent with a pattern associated with poorer prognosis. We also determined the prognostic significance of stromal CD8+ T cells in HIV-related lymphomas in a clinical population. We found that host HIV disease history, including low circulating CD4+ cell count and prior AIDS diagnosis were associated with the composition of tumor microenvironment. As such, early initiation of ART and maintenance of immune function may have an impact not only on the incidence of lymphomas but also on disease prognosis. These data suggest that antitumor immunity plays an important role in disease progression and treatment outcomes in HIV-infected patients, but it can be compromised. Patient management strategies directed at restoring immunosurveillance at the tumor microenvironment level may thus hold promise for treating HIV-related lymphomas.
The authors would like to thank Ms Wendy Leyden for programming support, and Ms Courtney Ellis and Ms Michelle McGuire for project management support.
Authors’ contribution: C.C. conceptualized the study. C.C., M.J.S. and J.S. led the study design. C.C. and M.J.S. led the collection of clinical data. J.S. and H.D.Z. performed pathology review and diagnosis confirmation. J.S. and B.C. performed laboratory assays and tumor marker data collection. L.X. and L.C. performed data cleaning, editing and statistical analyses. O.M., D.I.A. and R.H. assisted with the study design, data collection and result interpretation. All authors have critically reviewed and edited the article.
Source of funding: This work is supported by National Cancer Institute grant R01CA134234–01 Prognostic Markers for HIV-Positive Diffuse Large B-Cell Lymphoma.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2015 Wolters Kluwer Health, Inc.
diffuse large B-cell lymphoma; HIV; prognosis; stromal; tumor microenvironment