Abstract

Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell NHL characterized by a high relapse rate. Novel treatments capable of providing and/or sustaining more durable responses in MCL patients are clearly needed. Manipulation of the immune system to unleash its protective effect might induce durable responses in MCL. To effectively harness the immune system against MCL, it is important to understand how T-cells interact with malignant B-cells that reside where immune responses are normally initiated. In the present study, we evaluated the number and phenotype of T-cells present in the lymph nodes of 14 patients with MCL. Given the increasingly important role of T regulatory cells (Tregs) and the paucity of information regarding their role in MCL, we also evaluated if T-cells infiltrating the lymph node of MCL patients co-express CD4 and FoxP3. Our patients consisted of 1 woman and 13 men, age range from 49–78 (mean age 65), 6 previously treated with chemotherapy, and 8 de novo. There was heterogeneity in the CD3+ T cell populations in our patients (range 2.7–55% [mean 15.8%]). Double staining with CD4/FoxP3 (range 0.2–3.4% [mean 1.7%]) and CD8/FoxP3 (range 0–3.2% [mean 1.4%]) showed significant heterogeneity in both populations (Table 1). A significant portion of FoxP3 positive, CD4/CD8 negative cells were seen in several cases (range 0–16% [mean 4.9%]). Flow cytometry was run on all 14 cases to evaluate the T cell populations. Spearman non-Gaussian regression analysis (using GraphPad™ software) comparing the CD4/FoxP3+ and CD8/FoxP3+ cells to the total CD8 cells showed a negative correlation by both immunohistochemical and flow, confirming that as the Treg population increases the CD8 population decreases (Table 2). Correlating CD4 Treg with CD8 by flow cytometry and IHC indicated an inverse correlation in 7 of 14 cases. Only 1 case had a positive correlation. The remaining cases had no correlation. These findings suggest increasing FoxP3 populations in MCL could result in a decrease in CD8+ T cell immune response against the malignant cells. Future studies including the characterization of the non-CD4/CD8 FoxP3+ cells may help clarify the role of Tregs in MCL.

Table 1:

MCL T cell Populations

CD3+ FLOW (%)Total FoxP3 IHC (%)CD4/FoxP3+ IHC (%)CD8/FoxP3+ IHC (%)CD4+ IHC (%)CD8+ IHC (%)CD4+ FLOW (%)CD8+ FLOW (%)
6.5 3.2 1.8 0.4 6.4 7.8 
43 12.8 0.6 10.6 19.2 16 27 
16 4.4 0.2 0.8 8.8 15.4 11 
11 3.6 1.4 6.2 1.8 
8.4 3.4 0.8 1.4 17.6 11.2 1.6 3.9 
10 7.8 1.8 0.6 13.6 9.2 7.5 2.5 
26 12.4 3.4 2.4 15.8 16.8 20 0.1 
6.3 8.2 2.2 3.2 11.6 11 1.7 3.7 
55 8.6 3.4 21 21.6 30 25 
12 10.8 2.4 16.8 17 5.1 
8.4 4.6 1.6 1.2 17.6 18 5.1 3.2 
5.4 9.6 1.8 1.8 13.6 16 3.6 0.3 
2.7 2.2 0.8 1.4 3.8 3.4 0.8 1.9 
11 19 1.2 1.8 22 8.6 7.6 3.6 
CD3+ FLOW (%)Total FoxP3 IHC (%)CD4/FoxP3+ IHC (%)CD8/FoxP3+ IHC (%)CD4+ IHC (%)CD8+ IHC (%)CD4+ FLOW (%)CD8+ FLOW (%)
6.5 3.2 1.8 0.4 6.4 7.8 
43 12.8 0.6 10.6 19.2 16 27 
16 4.4 0.2 0.8 8.8 15.4 11 
11 3.6 1.4 6.2 1.8 
8.4 3.4 0.8 1.4 17.6 11.2 1.6 3.9 
10 7.8 1.8 0.6 13.6 9.2 7.5 2.5 
26 12.4 3.4 2.4 15.8 16.8 20 0.1 
6.3 8.2 2.2 3.2 11.6 11 1.7 3.7 
55 8.6 3.4 21 21.6 30 25 
12 10.8 2.4 16.8 17 5.1 
8.4 4.6 1.6 1.2 17.6 18 5.1 3.2 
5.4 9.6 1.8 1.8 13.6 16 3.6 0.3 
2.7 2.2 0.8 1.4 3.8 3.4 0.8 1.9 
11 19 1.2 1.8 22 8.6 7.6 3.6 
Table 2:

Spearman Rank Correlation

GroupSpearman Rank Correlation95% Confidence Interval
CD4/FoxP3+ vs. CD8 (IHC) 0.2788 −0.3115 to 0.7138 
CD4/FoxP3+ vs. CD8 (FLOW) −0.2614 −0.7045 to 0.3284 
CD8/FoxP3+ vs. CD8 (IHC) 0.2558 −0.3337 to 0.7105 
CD8/FoxP3+ vs. CD8 (FLOW) −0.2196 −0.6815 to 0.3673 
CD4/FoxP3+ vs. CD4 (IHC) 0.3448 −0.2440 to 0.7479 
CD4/FoxP3+ vs. CD4 (FLOW) 0.3636 −0.2237 to 0.7572 
CD8/FoxP3+ vs. CD4 (IHC) 0.4044 −0.1777 to 0.7769 
CD8/FoxP3+ vs. CD4 (FLOW) −0.2243 −0.6841 to 0.3630 
GroupSpearman Rank Correlation95% Confidence Interval
CD4/FoxP3+ vs. CD8 (IHC) 0.2788 −0.3115 to 0.7138 
CD4/FoxP3+ vs. CD8 (FLOW) −0.2614 −0.7045 to 0.3284 
CD8/FoxP3+ vs. CD8 (IHC) 0.2558 −0.3337 to 0.7105 
CD8/FoxP3+ vs. CD8 (FLOW) −0.2196 −0.6815 to 0.3673 
CD4/FoxP3+ vs. CD4 (IHC) 0.3448 −0.2440 to 0.7479 
CD4/FoxP3+ vs. CD4 (FLOW) 0.3636 −0.2237 to 0.7572 
CD8/FoxP3+ vs. CD4 (IHC) 0.4044 −0.1777 to 0.7769 
CD8/FoxP3+ vs. CD4 (FLOW) −0.2243 −0.6841 to 0.3630 

Author notes

Disclosure: No relevant conflicts of interest to declare.