This study has identified differences in immune cell composition of the diagnostic FL lymph node immune microenvironment and these have the potential for use as prognostic biomarkers in a routine histopathology setting.

An important hallmark of cancer progression is the ability of tumor cells to evade immune recognition. Understanding the relationship between neoplastic cells and the immune microenvironment should facilitate the design of improved immunotherapies. Here we identify impaired T-cell immunologic synapse formation as an active immunosuppressive mechanism in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We found a significant reduction in formation of the F-actin immune synapse in tumor-infiltrating T cells (P < .01) from lymphoma patients compared with age-matched healthy donor cells. Peripheral blood T cells exhibited this defect only in patients with leukemic-phase disease. Moreover, we demonstrate that this T-cell defect is induced after short-term tumor cell contact. After 24-hour coculture with FL cells, previously healthy T cells showed suppressed recruitment of critical signaling proteins to the synapse. We further demonstrate repair of this defect after treatment of both FL cells and T cells with the immunomodulatory drug lenalidomide. Tissue microarray analysis identified reduced expression of the T-cell synapse signature proteins, including the cytolytic effector molecule Rab27A associated with poor prognosis, in addition to reduced T-cell numbers and activity with disease transformation. Our results highlight the importance of identifying biomarkers and immunotherapeutic treatments for repairing T-cell responses in lymphoma.

We present here a genome-wide map of abnormalities found in diagnostic samples from 45 adults and adolescents with acute lymphoblastic leukemia (ALL). A 500K SNP array analysis uncovered frequent genetic abnormalities, with cryptic deletions constituting half of the detected changes, implying that microdeletions are a characteristic feature of this malignancy. Importantly, the pattern of deletions resembled that recently reported in pediatric ALL, suggesting that adult, adolescent, and childhood cases may be more similar on the genetic level than previously thought. Thus, 70% of the cases displayed deletion of one or more of the CDKN2A, PAX5, IKZF1, ETV6, RB1, and EBF1 genes. Furthermore, several genes not previously implicated in the pathogenesis of ALL were identified as possible recurrent targets of deletion. In total, the SNP array analysis identified 367 genetic abnormalities not corresponding to known copy number polymorphisms, with all but two cases (96%) displaying at least one cryptic change. The resolution level of this SNP array study is the highest used to date to investigate a malignant hematologic disorder. Our findings provide insights into the leukemogenic process and may be clinically important in adult and adolescent ALL. Most importantly, we report that microdeletions of key genes appear to be a common, characteristic feature of ALL that is shared among different clinical, morphological, and cytogenetic subgroups. A cute lymphoblastic leukemia (ALL) occurs at all ages but displays a bimodal distribution of incidence, with one peak in early childhood and a second in patients older than 50 years (1). For adult ALL, the yearly incidence is Ϸ2 per 100,000, with Ϸ75% of the cases being B lineage and the remainder of T cell origin (1, 2). The most prominent prognostic factors are age, white blood cell count (WCC), and different genetic abnormalities, with younger age and lower WCC being associated with an improved outcome (3, 4). Most adults, however, are considered to be high-risk, and the long-term disease-free survival rates are Ͻ40% (1, 3-5). This is in stark contrast to pediatric ALL, where refined treatment regimens have resulted in cure rates approaching 80% (6, 7). Treatment of adolescents (15-21 years old) on pediatric protocols has resulted in an increased overall survival but is still far from the outstanding results achieved in children (8). Hence, there is a need for novel prognostic markers in adult and adolescent ALL to allow a better risk stratification of these patients and to identify new treatment targets.Whereas genetic abnormalities in pediatric ALL are widely used in clinical practice for risk stratification purposes, most treatment protocols in adult ALL consider only the presence or absence of the Philadelphia chromosome, t(9;22)(q34;q11.2). The t(9;22), which results in the BCR/ABL1 fusion gene, is found in 20-30% of adult B cell precursor cases and is an adverse prognostic indicator (9-12). Other recurrent rearrangements include the t(4;11)(q21;q23) forming a MLL/AFF1 (prev...