Abstract

Mantle cell lymphoma is a non-Hodgkin lymphoma with, in general, a poor prognosis. A minor subset of patients with an indolent disease course has however been recognized (1,2). The various growth patterns of MCL, i.e. mantle zone (MZ), nodular (N) or diffuse (D) is assumed to correlate to stage and to disease course. The genetic aberrations underlying the pathogenesis are well defined and correlate to high tumour cell proliferation and poor prognosis. However, the effect of the lymphoma microenvironment in disease development and sustainability is largely unknown.

We have used flow cytometry to investigate the non-malignant cell composition of the lymph node microenvironment in a population-based cohort of 154 MCL cases diagnosed from January 1, 1998 to December 31, 2012. Flow cytometry analyses of lymph nodes, performed as part of the diagnostic process, were used to evaluate percentages of tumour cells, remaining non-malignant B-cells and T-cell subsets (CD3+, CD3+CD4+, CD3+CD8+). As lymph node T-cell numbers reflect a high tumor load in the lymph node we also investigated the CD4/CD8 ratio, which is not dependent on T-cell percentage. Data from 26 non-malignant lymph nodes were used for comparison. T-cell percentages are shown in Table 1. Clinical and other pathological parameters of the MCL cases, including MIPI, cell morphology, tumor growth pattern and cell proliferation were also evaluated. Indolent disease (n=15), defined here as requirement of treatment > two years from diagnosis, was associated with higher amount of CD3, CD3+CD4+ and higher CD4/CD8 ratio (p=0.0429, p=0.0211 and p= 0.0032 respectively). Higher tumor cell proliferation correlated negatively with the CD4/CD8 ratio (p= 0.0007). There was a significant difference in CD3 percentages between reactive lymph nodes and MCL irrespective of growth pattern (all p<0.001). Within the entity of MCL, CD3 percentage were higher in MZ growth pattern compared to N and D (p=0.014 and p<0.001, respectively). CD3 percentages were also higher in N compared to D growth pattern (p=0.0086). CD4/CD8 ratio decreased according to growth pattern (MZ compared to N p=0.048, MZ compared to D p=0.003). Blastoid and classical MCL variants did not differ significantly in amount of CD3, CD3+CD4+, CD3+CD8+, CD19 or CD4/CD8 ratio (all p>0.05). Furthermore, male sex negatively correlated with CD4/CD8 ratio (p=0.0268). Age was not associated to T-cell percentages, CD4/CD8 ratio or growth pattern. In survival analysis a high CD4/CD8 ratio was positively correlated with OS (p= 0.0175).

Table 1

T-cell percentages (% of mononuclear cells) and CD4/CD8 ratio in reactive lymph nodes and MCL with different growth patterns (marginal zone (MZ), nodular (N) and diffuse (D)) (median, range).

 CD3 CD4 CD8 CD4/CD8 
Reactive lymph nodes n=26 52.9 (17.6-75.6) 39.6 (14.1-63.4) 10.0 (2.4-19.2) 4.2 (2.1-6.9) 
MCL MZ n=25 30.4 (10.9-84.0) 17.4 (7.4-63.2) 7.9 (1.2-21.1) 3.1 (0.9-7.7) 
MCL N n=27 16.7 (2.3-71.4) 9.6 (1.1-58.9) 5.4 (1.1-15.2) 1.8 (0.6-8.6) 
MCL D n=46 9.9 (2.0-43.7) 5.5 (0.7-37.0) 4 (0.4-18.1) 1.6 (0.4-10.4) 
 CD3 CD4 CD8 CD4/CD8 
Reactive lymph nodes n=26 52.9 (17.6-75.6) 39.6 (14.1-63.4) 10.0 (2.4-19.2) 4.2 (2.1-6.9) 
MCL MZ n=25 30.4 (10.9-84.0) 17.4 (7.4-63.2) 7.9 (1.2-21.1) 3.1 (0.9-7.7) 
MCL N n=27 16.7 (2.3-71.4) 9.6 (1.1-58.9) 5.4 (1.1-15.2) 1.8 (0.6-8.6) 
MCL D n=46 9.9 (2.0-43.7) 5.5 (0.7-37.0) 4 (0.4-18.1) 1.6 (0.4-10.4) 

In conclusion, our data show that the normal lymph node microenvironment is better preserved in indolent MCL and MCL with mantle zone growth pattern. The CD4/CD8 ratio is independent of lymph node tumor burden and high CD4/CD8 ratio was found to correlate with better OS. MCL tumor cells have recently been reported to impair T-cell responses (3). Our results could reflect a disease evolution towards lower tumor cell dependency on signals from the microenvironment and/or as a lymphoma mediated suppression of immune mechanisms for tumor control in aggressive MCL.

References:

1. Martin, P. et al. Outcome of deferred initial therapy in mantle-cell lymphoma. J. Clin. Oncol., 2009, 27(8): p. 1209–13

2. Nygren, L. et al. Prognostic role of SOX11 in a population-based cohort of mantle cell lymphoma. Blood, 2012. 119(18): p- 4125–23.

3. Wang, L. et al. Immune evasion evasion of mantle cell lymphoma: expression of B7-H1 leads to inhibited T-cell response to and killing of tumor cells. Haematologica, 2013.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

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Asterisk with author names denotes non-ASH members.