Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4 + and CD8 + T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation.These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.
Key Points• T cells from patients with CLL exhibit features of T-cell exhaustion.• These findings exclude CMV as the sole cause of T-cell defects in CLL.T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. It is not defined whether exhaustion contributes to T-cell dysfunction observed in chronic lymphocytic leukemia (CLL). We investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8 ؉ and CD4 ؉ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160, and PD1, with expansion of a PD1 ؉ BLIMP1 HI subset. These molecules were most highly expressed in the expanded population of effector T cells in CLL. CLL CD8 ؉ T cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-␥ and TNF␣ and increased expression of TBET, and normal IL2 production. These defects were not restricted to expanded populations of cytomegalovirus (CMV)-specific cells, although CMV seropositivity modulated the distribution of lymphocyte subsets, the functional defects were present irrespective of CMV serostatus. Therefore, although CLL CD8 ؉ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. These findings also exclude CMV as the sole cause of T-cell defects in CLL. (Blood. 2013;121(9):1612-1621)
Background & Aims Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic microenvironment that contains many different immune cells. Activated pancreatic stellate cells (PSCs) contribute to the desmoplasia. We investigated whether distinct stromal compartments are differentially infiltrated by different types of immune cells. Method We used tissue microarray analysis to compare immune cell infiltration of different pancreatico-biliary diseased tissues (PDAC, ampullary carcinoma, cholangiocarcinoma, mucinous cystic neoplasm, chronic inflammation, and chronic pancreatitis), and juxtatumoral stromal (<100 μm from tumor) and panstromal compartments. We investigated the association between immune infiltrate and patient survival times. We analyzed T-cell migration and tumor infiltration in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) mice, and the effects of all-trans retinoic acid (ATRA) on these processes. Results Juxtatumoral compartments in PDAC samples from 2 independent groups of patients contained increased numbers of myeloperoxidase+ and CD68+ cells, compared with panstromal compartments. However, juxtatumoral compartments of PDACs contained fewer CD8+, FoxP3+, CD56+, or CD20+ cells than panstromal compartments, a distinction absent in ampullary carcinomas and cholangiocarcinomas. Patients with PDACs that had high densities of CD8+ T-cells in the juxtatumoral compartment had longer survival times than patients with lower densities. In KPC mice, administration of ATRA, which renders PSCs quiescent, increased numbers of CD8+ T-cells in juxtatumoral compartments. We found that activated PSCs express cytokines, chemokines, and adhesion molecules that regulate T-cell migration. In vitro migration assays showed that CD8+ T-cells from PDAC patients had increased chemotaxis towards activated PSCs, which secrete CXCL12, compared with quiescent PSC or tumor cells. These effects could be reversed by knockdown of CXCL12 or treatment of PSCs with ATRA. Conclusion Based on studies of human PDAC samples and KPC mice, activated PSCs appear to reduce migration of CD8+ T-cells to juxtatumoral stromal compartments, preventing their access to cancer cells. Deregulated signaling by activated PSCs could prevent an effective anti-tumor immune response.
Cancer immune evasion is an emerging hallmark of disease progression. We have demonstrated previously that impaired actin polymerization at the T-cell immunologic synapse is a global immune dysfunction in chronic lymphocytic leukemia (CLL). Direct contact with tumor cells induces defective actin polarization at the synapse in previously healthy T cells, but the molecules mediating this dysfunction were not known. In the present study, we show via functional screening assays that CD200, CD270, CD274, and CD276 are coopted by CLL cells to induce impaired actin synapse formation in both allogeneic and autologous T cells. We also show that inhibitory ligand-induced impairment of T-cell actin dynamics is a common immunosuppressive strategy used by both hematologic (including lymphoma) and solid carcinoma cells. This immunosuppressive signaling targets T-cell Rho-GTPase activation. Of clinical relevance, the immunomodulatory drug lenalidomide prevented the induction of these defects by down-regulating tumor cell-inhibitory molecule expression. These results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations. These findings should contribute to the design of immunotherapeutic strategies to reverse T-cell tolerance in cancer. (Blood. 2012;120(7):1412-1421) IntroductionTargeted immunotherapy has the potential to affect cancer treatment and target drug-resistant tumor subclones. 1 Chronic lymphocytic leukemia (CLL) is a good model with which to test novel immunotherapeutic approaches 2 and to examine tumor cell interactions with immune cells. 3 The intrinsic nature of CLL and other leukemias means that circulating T cells and tumor cells are in regular contact interactions. Our previous gene-expression profiling studies in peripheral blood CD4 ϩ and CD8 ϩ T-cell populations from CLL patients revealed profound dysregulation in multiple gene pathways, including the actin cytoskeleton. 4 Functional T-cell immunologic synapses control assembly of signaling complexes between the Ag-ligated TCR and the cytoskeletal signaling layer, and is dependent on polymerized filamentous actin (F-actin). 5 T cells isolated from CLL patients have defective F-actin polymerization and immune synapse formation at the contact site with APCs, steps required for activation and CTL effector function. 6,7 Direct contact with CLL tumor cells induces these molecular and functional defects in previously healthy T cells in vitro and in vivo. 4,6,8 This tumor-immunosuppressive mechanism likely contributes to disease progression and blocks the effectiveness of current immunotherapy approaches. Therefore, it is essential to elucidate the signaling mechanisms mediating T-cell dysfunction in CLL to improve our understanding of how cancer cells evade immune recognition and then use this knowledge to improve immunotherapy strategies.In the present study, we used human CLL as a model cance...
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