Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy

Abstract

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.

Higher response to lenalidomide in relapsed/refractory diffuse large B‐cell lymphoma in nongerminal center B‐cell–like than in germinal center B‐cell–like phenotype

“…13,14,16 Recently, lenalidomide was found to modulate T-cell functions and repair F-actin-mediated T-cell immune synapses against primary tumor cells in chronic lymphocytic leukemia, follicular lymphoma, and DLBCL. 17 Two phase 2 clinical trials (NHL-002 and NHL-003) were previously conducted to evaluate efficacy and safety of lenalidomide monotherapy in relapsed/refractory aggressive lymphoma (including DLBCL). 11,12 In these studies, the overall response rates (ORRs) in patients with DLBCL were 19% to 28%, including 7% to 12% complete responses (CRs)/unconfirmed complete responses.…”

Lectin-like transcript 1 is a marker of germinal center-derived B-cell non-Hodgkin's lymphomas dampening natural killer cell functions

“…Several mechanisms have been identified which lead to inefficient antitumor responses. These include downregulation of MHC class I and II, 18,19 loss of CD58, 19 disruption of the T cell/malignant B cell synapse, 20 T cell exhaustion 21 or recruitment/amplification of regulatory T cells. [22][23][24] Expression of ligands of inhibitory coreceptors has been detected on lymphomas and can subvert NK and T cell immune functions.…”

Follicular Lymphoma: The Role of the Tumor Microenvironment in Prognosis

“…21 However, understanding the relationship between the neoplastic cells and the various cellular components of the microenvironment will be crucial for developing therapeutics aimed at the microenvironment in the battle against FL. At present, the proposed classes of new agents for manipulation of the microenvironment surrounding FL cells include immunomodulatory drugs, that is, lenalidomide, [22][23][24][25][26][27][28] as well as immune checkpoint blockers, such as those targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) 29 or the programed death 1 (PD1) 30 axes. Further investigations will be needed to improve the outcomes of FL patients who have been treated with the chimeric anti-CD20 monoclonal antibody during the rituximab era.…”