A Review of New Findings in Adult T-cell Leukemia–Lymphoma: A Focus on Current and Emerging Treatment Strategies

<p><strong>Article full text</strong></p> <br> The full text of this article can be found <a href="https://link.springer.com/article/10.1007/s12325-018-0658-4"><b>here</b>.</a><br> <br> <strong>Provide enhanced digital features for this article</strong><br> If you are an author of this publication and would like to provide additional enhanced digital features for your article then please contact <u>[email protected]</u>.<br> <br> The journal offers a range of additional features designed to increase visibility and readership. All features will be thoroughly peer reviewed to ensure the content is of the highest scientific standard and all features are marked as ‘peer reviewed’ to ensure readers are aware that the content has been reviewed to the same level as the articles they are being presented alongside. Moreover, all sponsorship and disclosure information is included to provide complete transparency and adherence to good publication practices. This ensures that however the content is reached the reader has a full understanding of its origin. No fees are charged for hosting additional open access content.<br> <br> Other enhanced features include, but are not limited to:<br> • Slide decks<br> • Videos and animations<br> • Audio abstracts<br> • Audio slide

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a<p>Graduation level. M (mean); S.D. (standard deviation); N: number of patients.</p

Features of cognitive impairment in mastocytosis.

<p>In the ordinate axis each line represents a patient. In the abscissa axis the severity of the cognitive impairment is represented for each column (1: slight; 2: moderate; 3: severe). Columns displays features of cognitive impairment observed (A: auditory; V: visual; I: immediate; D: delayed; WM: working memory). Black marks gives the feature and the severity of cognitive impairment for each patient. Among the 22 patients WM impairment as the most frequent concerning 16 patients (10 with WM alone and 6 associated to auditory and/or visual impairment. In our sample (n = 57), 22 patients (38.6%) were diagnosed with cognitive impairment. 12 patients (59.1%) have slight impairment; 7 (27.3%) have moderate impairment and severe impairment affected 3 (13.6%) patients.</p

Cognitive impaired patients are no more depressed than patients without cognitive impairment.

<p>We performed an unpaired t-test to compare depression scores of patients with and without cognitive impairment. In the group of patients diagnosed with cognitive impairment mean depression score was 15.8 (SD = 9.09). In the group without cognitive impairment diagnosis the mean depression score was 12.48 (SD = 6.59).The analysis showed no significant difference between the groups (t = 1.296; p = 0.200). CI: cognitive impairment; ns: not significant.</p

Neuropilin-1 Expression Characterizes T Follicular Helper (Tfh) Cells Activated during B Cell Differentiation in Human Secondary Lymphoid Organs

<div><p>T follicular helper (Tfh) cells play an essential role in the development of antigen-specific B cell immunity. Tfh cells regulate the differentiation and survival of activated B cells outside and inside germinal centers (GC) of secondary lymphoid organs. They act through cognate contacts with antigen-presenting B cells, but there is no current marker to specifically identify those Tfh cells which productively interact with B cells. Here we show that neuropilin 1 (Nrp1), a cell surface receptor, is selectively expressed by a subset of Tfh cells in human secondary lymphoid organs. Nrp1 expression on Tfh cells correlates with B cell differentiation <i>in vivo</i> and <i>in vitro</i>, is transient, and can be induced upon co-culture with autologous memory B cells in a cell contact-dependent manner. Comparative analysis of <i>ex vivo</i> Nrp1⁺ and Nrp1^- Tfh cells reveals gene expression modulation during activation. Finally, Nrp1 is expressed by malignant Tfh-like cells in a severe case of angioimmunoblastic T-cell lymphoma (AITL) associated with elevated terminal B cell differentiation. Thus, Nrp1 is a specific marker of Tfh cells cognate activation in humans, which may prove useful as a prognostic factor and a therapeutic target in neoplastic diseases associated with Tfh cells activity. </p> </div

Tonsillar Nrp1⁺ CD4⁺ T cells have a Tfh phenotype <i>in</i><i>vivo</i>.

<p>(A) Representative flow cytometry analysis of Nrp1 and CD25, Foxp3, CD69, CCR7 and CD45RA co-expression on tonsillar CD3⁺ CD4⁺ T cells population. (B) CD25 and Foxp3 co-expression on tonsillar CD3⁺ CD4⁺ Nrp1⁺ and Nrp1^- T cell populations. (C-F) Nrp1 expression on tonsillar Tfh cells and non-Tfh cells, defined as CD3⁺ CD4⁺ CXCR5⁺ PD-1⁺ and CD3⁺ CD4⁺ CXCR5^- PD-1^- respectively (C-D), or CD3⁺ CD4⁺ CXCR5⁺ ICOS^hi and CD3⁺ CD4⁺ CXCR5^- ICOS^lo respectively (E-F). Numbers in flow cytometry plots indicate the mean percentage ± SD of Tfh cells in CD4⁺ T cells (left) and of Nrp1⁺ cells in Tfh cells (middle) and non-Tfh cells (right) (n=10 tonsils). (G-H) Nrp1 expression on tonsillar CD3⁺ CD4⁺ CXCR5⁺ CD57⁺ and CD3⁺ CD4⁺ CXCR5^- CD57^- Tfh cells. Data were compared using Student’s impaired t-test (**: p≤0.01, ***: p≤0.001).</p

Nrp1 expression by Tfh cells requires cognate B cell contact and reflects Tfh activity <i>in</i><i>vitro</i>.

<p>(A-C) Nrp1^- Tfh, Nrp1⁺ Tfh and non-Tfh cells were sorted as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0085589#pone-0085589-g001" target="_blank">Figure 1</a> and cultured with autologous B cells in the absence of exogenous stimuli. (A) Representative expression of CD25 and Nrp1 on T cells (top) and B cells (bottom) after 5 days of culture. (B) Percentage of Nrp1⁺ cells among T or B cells after 5 days of culture. (C) Percentage of Nrp1⁺ cells among T cells after 24, 48 and 72 hours of culture. In B and C, representative data from one out of three distinct experiments are shown. (D) Nrp1 expression on sorted Nrp1⁺ Tfh cells after 5 days of culture alone (dark line) or with autologous B cells (shaded histogram). (E-F) Nrp1^- Tfh cells were cultured with autologous B cells in the absence or presence of a transwell membrane separating the two cell types. (E) Representative Nrp1 expression on T cells after 5 days of culture. (F) Number of live B cells per well after 5 days of culture. (G-J) Autologous or allogeneic cocultures were performed using Nrp1^- Tfh and B cells sorted from two distinct tonsils (a) and (b). (G) Nrp1 expression on T cells after 5 days of culture. Data represent one experiment with triplicate wells and are representative of three distinct experiments. (I-J) IgG production in culture supernatant after 10 days of culture. (K-L) Sorted naive, GC or memory B cells were cultured in the absence or presence of autologous CXCR5^- Nrp1^- non-Tfh cells or CXCR5⁺ Nrp1^- Tfh cells. (K) Nrp1 expression on non-Tfh cells and Nrp1^- Tfh cells after 4 days of culture. (L) IgG production in culture supernatants after 14 days of culture. Data were compared using Student’s impaired t-test (*: p≤0.05, **: p≤0.01).</p

Gene expression profiles of Nrp1^- and Nrp1⁺ Tfh cells.

<p>Nrp1^- and Nrp1⁺ Tfh cells were sorted from 5 distinct tonsils and analyzed for gene expression as described in Materials and Methods. Gene expression (normalized to ACTB) of a selection of relevant transcription factors (A), cytokines and chemokines (B), co-stimulatory, homing and cytokine receptors (C) in Nrp1^- and Nrp1⁺ Tfh cells is shown here. Numbers above bars indicate fold change and p-value (paired student’s t test). </p

Correlation between Nrp1 expression and germinal center activity in secondary lymphoid organs.

<p>Tonsils and non-malignant reactive lymph nodes were compared for their percentages of Tfh cells (A), Nrp1⁺ T cells (B) and Nrp1^- Tfh cells (D) in CD4⁺ T cells and for their percentage of Nrp1⁺ cells in Tfh cells (C) . (E-L) Correlation between the percentage of Tfh cells (E and I), Nrp1⁺ T cells (F and J), Nrp1⁺ cells in Tfh cells (G and K), and Nrp1^- Tfh cells (H and L) and the percentage of GC B cells (E-H) or plasmablasts (I-L) among CD19⁺ cells in tonsils (full circle) and non-malignant reactive lymph nodes (white circle). (M-P) Correlation between the percentage of Nrp1⁺ cells in Tfh cells (M and O), or the percentage of Nrp1^- Tfh cells (N and P), and the percentage of GC B cells (M-N) or plasmablasts (O-P) among CD19⁺ cells only in tonsils only. Data were compared using Student’s impaired t-test (*: p≤0.05, ***: p≤0.001) (A-D). For correlation analyses, the correlation coefficient r² and the associated p-value are shown.</p

Tonsillar Nrp1⁺ CD4⁺ T cells support survival and Ig production of B cells <i>in</i><i>vitro</i>.

<p>(A) Flow cytometry analysis of Nrp1^- Tfh (CXCR5⁺ Nrp1^-: i), Nrp1⁺ Tfh (CXCR5⁺ Nrp1⁺: ii) and non-Tfh cells (CXCR5^- Nrp1^-: iii). (B-C) These three T cell subsets were cultured with B cells without exogenous stimulation, and compared for their ability to maintain B-cell survival after 5 days (B) and to induce the production of IgG, IgA and IgM (C) after 10 days of culture. Representative data from one out of four experiments are shown. Data were compared using Student’s impaired t-test (ns: not significant, *: p≤0.05, **: p≤0.01).</p