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. 2022 Oct 13;3(4):1165-1171.
doi: 10.1002/jha2.549. eCollection 2022 Nov.

Aggressive, early resistant and relapsed mantle cell lymphoma distinct extrinsic microenvironment highlighted by transcriptome analysis

Yannick Le Bris  1   2 , Adeline Normand  3 , Louise Bouard  4 , Audrey Ménard  1 , Céline Bossard  3 , Anne Moreau  3   5 , Marie C Béné  1   2
Affiliations

Aggressive, early resistant and relapsed mantle cell lymphoma distinct extrinsic microenvironment highlighted by transcriptome analysis

Yannick Le Bris et al. EJHaem. .

Abstract

Immunotherapy strategies relying on innate or adaptive immune components are increasingly used in onco-haematology. However, little is known about the infiltrated lymph nodes (LN) or bone marrow (BM) landscape of mantle cell lymphoma (MCL). The original transcriptomic approach of reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was applied here to explore the expression of 24 genes of interest in MCL at diagnosis (21 LN and 15 BM) or relapse (18 LN). This allowed us to identify that at baseline, samples from MCL patients with an aggressive morphology (i.e. blastoid or pleomorphic) or a high proliferative profile, displayed significantly higher monocyte/macrophage-associated transcripts (CD14 and CD163) in LN and BM. Regarding T-cells, aggressive MCL forms had significantly lower amounts of LN CD3E transcripts, yet an increased expression of cytotoxic markers in LN (CD8) and BM (CD94). A very high-risk group with early treatment resistance displayed, at diagnosis, high proliferation (KI67) and high macrophages and cytotoxic transcript levels. Post-immunochemotherapy relapsed samples revealed lower levels of T- and natural killer-cells markers, while monocyte/macrophage markers remained similar to diagnosis. This study suggests that rapid analysis of MCL microenvironment transcriptome signatures by RT-MLPA could allow for an early distinction of patient subgroups candidates for adapted treatment strategies.

Keywords: macrophages; mantle cell lymphoma; microenvironment; relapse; resistance.

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Conflict of interest statement

The authors declare they have no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Expression profiles of extrinsic markers in the context of mantle cell lymphoma (MCL) patients with poor prognosis features. (A) Comparison of CD14, CD163 and MCSF transcript levels measured in lymph nodes (LN) or bone marrow (BM) in the context of blastoid MCL or not. (B) Comparison between aggressive and non‐aggressive morphology tumoral LN, of the expression of T‐cell CD3 and CD8 markers. (C) Comparison between highly proliferative tumoral LN or not, of the expression of immune checkpoints. ** p < 0.001
FIGURE 2
FIGURE 2
Baseline expression profiles of intrinsic and extrinsic transcripts in mantle cell lymphoma (MCL) lymph nodes according to the p53 status. P53 disruption was defined by the detection of TP53 mutation or p53 aberrant expression in immunohistochemistry (IHC). ** p < 0.001
FIGURE 3
FIGURE 3
Impact of intrinsic/extrinsic gene expression on outcomes. (A) Expression profile of KI67, CD163 and PD1 in the context of refractory or early relapse < 1 year. (B) Unsupervised hierarchical cluster analysis of the expression of CD168, CD8, PD1 and KI67 genes (signal intensity), aggressive morphology (orange) and p53 disruption (purple) compared to refractory/early relapse (red). *p < 0.05; ** p < 0.001; *** p < 0.0001; ns: Not significant (i.e. p > 0.05)
FIGURE 4
FIGURE 4
Diagnosis (D)/relapse (R) comparison profile in lymph nodes of transcript expression levels in unpaired samples of genes specific for monocyte/macrophages (CD14 and CD163), total T cells (CD3), helper (CD40L) lymphocytes and cytotoxic cells (CD8 and CD94). *p < 0.05; ** p < 0.001; *** p < 0.0001
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References

    1. Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, et al. Rituximab after autologous stem‐cell transplantation in mantle‐cell lymphoma. N Engl J Med. 2017;377(13):1250–60. - PubMed
    1. Gressin R, Daguindau N, Tempescul A, Moreau A, Carras S, Tchernonog E, et al. A phase 2 study of rituximab, bendamustine, bortezomib and dexamethasone for first‐line treatment of older patients with mantle cell lymphoma. Haematologica 2019;104(1):138–46. - PMC - PubMed
    1. Hoster E, Rosenwald A, Berger FO, Bernd H‐W, Hartmann S, Loddenkemper C, et al. Prognostic value of Ki‐67 index, cytology, and growth pattern in mantle‐cell lymphoma: results from randomized trials of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2016;34(12):1386–94. - PubMed
    1. Le Bris Y, Magrangeas F, Moreau A, Chiron D, Theisen O, Pichon O, et al. Whole genome copy number analysis in search of new prognostic biomarkers in first‐line treatment of mantle cell lymphoma. A study by the LYSA group. Hematol Oncol. 2020;38(4):446–55. - PubMed
    1. Delfau‐Larue MH, Klapper W, Berger F, Jardin F, Briere J, Salles G, et al. High‐dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma. Blood 2015;126(5):604–11. - PubMed

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