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, 44 (3), 218-225

Hodgkin Lymphoma: A Complex Metabolic Ecosystem With Glycolytic Reprogramming of the Tumor Microenvironment


Hodgkin Lymphoma: A Complex Metabolic Ecosystem With Glycolytic Reprogramming of the Tumor Microenvironment

Lekha Mikkilineni et al. Semin Oncol.


Background: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes.

Methods: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells.

Results: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature.

Conclusion: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.

Keywords: Hodgkin lymphoma; glycolysis; ketone bodies; lactate; mitochondria; oxidative phosphorylation.

Conflict of interest statement

The authors disclose no potential conflicts of interest


Fig. 1
Fig. 1. TOMM20, MCT1 and MCT4 staining in classical Hodgkin lymphoma (cHL)
Samples were stained and the intensity was assessed in cancer cells (HRS) and non-cancer cells within tumors. Note that the neoplastic cells in cHL have high expression of TOMM20 and MCT1 with low expression of MCT4. The stromal cells have an opposite pattern with low expression of TOMM20 and MCT1 with high expression of MCT4.
Fig. 2
Fig. 2. MCT1 and CD68 double labeling and MCT4 and CD68 double labeling in cHL
A negative control is shown in addition to the MCT1 and MCT4 double labeling with the macrophage marker CD68 by immunohistochemistry. Note that cancer cells express MCT1 (brown) while as the macrophages that express CD68 (red) do not express MCT1. Also, note that macrophages expressing CD68 (red) express MCT4 (brown) while as the cancer cells do not express MCT4.
Fig. 3
Fig. 3. CD68 and MCT1 staining by immunofluorescence in cHL
Immunofluorescence was performed on cHL samples staining for CD68 in green, MCT1 in red and DAPI blue counterstain to highlight nuclei. Note that CD68 macrophages do not stain for MCT1 since the red and green stains are not found on the same cells.
Fig. 4
Fig. 4. TOMM20, MCT1 and MCT4 staining patterns in cHL and outcomes
Progression free survival was graphed according to whether the tumor sample had high or low metabolic heterogeneity. High metabolic heterogeneity was defined as having high TOMM20 and MCT1 expression in cancer cells (HRS) and high MCT4 in tumor associated macrophages (TAMs). Specifically, high metabolic heterogeneity was defined as 2+ TOMM20 and 2+MCT1 in HRS and 2+MCT4 in TAMs. Any other expression pattern was defined as low metabolic heterogeneity. Note that high metabolic heterogeneity in cHL tumors is associated with shorter progression free survival (p<0.05).
Fig. 5
Fig. 5. Model of Cancer-Macrophage Metabolic Heterogeneity in cHL
A model of two-compartment tumor metabolism with neoplastic-macrophage metabolic heterogeneity is shown. The tumor-associated macrophages (TAMs) have high MCT4 expression, which is consistent with high generation and release of monocarboxylates and low mitochondrial metabolism. The neoplastic cells in cHL or Hodgkin/Reed Sternberg cells (HRS) have high MCT1 expression, which is consistent with high utilization of monocarboxylates. HRS also have high mitochondrial metabolism with high TOMM20 expression.

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