Abstract
Background: Advances in lymphoma therapy have led to improved survival rates for both Hodgkin and Non-Hodgkin lymphoma patients. This has resulted in a large and ever increasing population of lymphoma survivors. Depending on their disease and treatment history, these patients are known to be at risk for late cardiopulmonary effects, endocrine abnormalities, second malignancies, and psychosocial sequelae. However, little is known about the immune health of lymphoma survivors. Lymphoma itself perturbs the immune system. Additionally, lymphoma patients receive many immune-modulating therapies, such as rituximab, B- and T-cell signaling inhibitors, and stem cell transplants. We hypothesize that these interventions produce detectable long-term immune alterations in lymphoma survivors.
Methods: To determine whether altered immune phenotypes are detectable in lymphoma survivors, we used mass cytometry by time of flight (CyTOF) to broadly profile peripheral blood mononuclear cells (PBMCs) of a homogenously treated population of 8 mantle cell lymphoma survivors and compared these to PBMCs from 9 age-matched healthy donors. The data was normalized and analyzed visually using manual gating and viSNE for dimensionality reduction and subsequently with the CITRUS algorithm for unbiased statistical comparisons.
Results: All of the mantle cell lymphoma patients had undergone intensive induction chemotherapy followed by autologous stem cell transplant. Peripheral blood was collected on average 2.3 years after the end of therapy from patients confirmed to be free of disease. There were no significant differences between the proportions of T-cells, B-cells, monocytes, NK cells, or NK/T-cells among the peripheral blood mononuclear cells (PBMCs) of lymphoma survivors and healthy donors, but the heterogeneity among patients was notably higher than among controls. On average, lymphoma survivors had significantly fewer CD4 T-cells compared to healthy donors (p=0.006; Figure 1A) and these cells were skewed toward a memory phenotype compared to the CD4+ population in controls (p=0.0001 comparing proportion naïve, p=0.0034 comparing proportion effector memory; Figure 1B), a finding that correlated with time from end of therapy. CD8+ T-cells of lymphoma survivors were more frequently CD28-CD57+ (p=0.028), a phenotype that has been associated with chronic antigen experience. Unbiased analysis using CITRUS confirmed the above findings and additionally found IL7R-alpha to be differentially expressed between patient and control T-cells. This finding was confirmed by manual gating, where IL7R-alpha expression was found to be significantly decreased on both CD4+ T-cells (p=0.0007) and CD8+ T-cells (p=0.0001) in patients compared to controls (Figure 1C).
Conclusions: Survivors of mantle cell lymphoma have evidence of altered peripheral blood immunophenotypes years after completing treatment, possibly reflecting long-term effects of their exposure to lymphoma and its immune modulating treatments. Such derangements may lead to clinical immune dysfunction, a focus of planned future investigations.
No relevant conflicts of interest to declare.
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