Nodal presentation of nasal-type NK/T-cell lymphoma. Report of two cases with fine needle aspiration cytology findings

BACKGROUND: Epstein-Barr virus (EBV)-associated NK/T-cell lymphoma typically occurs in extranodal sites, such as nasal cavity, nasopharynx, gastrointestinal tract, skin, testis and salivary gland. Secondary lymph node involvement is rarely encountered until late in the disease course. The fine needle aspiration cytology of NK/T-cell lymphoma with a nodal presentation has not been described before. CASES: Two cases of nasal-type (extranasal) NK/T-cell lymphoma with a nodal presentation were seen at Pamela Youde Nethersole Eastern Hospital, Hong Kong. Both patients presented with submandibular lymph node enlargement but unremarkable peripheral blood and bone marrow findings. Fine needle aspiration cytology was available in both cases, showing a heterogeneous population of small to medium-sized lymphoid cells, follicular center cells, plasma cells, eosinophils and some histiocytes. The medium-sized lymphoid cells showed readily discernible nuclear atypia with an irregular nuclear outline. Cell block sections revealed occasional lymphoid cells with pleomorphic nuclei. Immunocytochemical study confirmed the presence of CD56-positive lymphoma cells. In situ hybridization for EBV-encoded RNA also revealed positive nuclear signals. Histologic examination of the surgical biopsies showed interfollicular expansion by malignant lymphoid cells. Immunoglobulin heavy chain gene and T-cell receptor gene rearrangement studies demonstrated a germline pattern, confirming the putative NK (natural killer cell), non-B and non-T lineage of the lymphoma cells. CONCLUSION: Nodal presentation of NK/T-cell lymphoma, though rare, is diagnosable on the basis of fine needle aspiration biopsy alone, especially in view of its distinctive immunophenotype and EBV association. Recognition of the subtle but definite cytologic atypia of malignant lymphoid cells and presence of an appropriate background (including more eosinophils than usual), together with proper application of ancillary techniques, is crucial to arriving at a correct diagnosis.     

Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine T cells.

The phosphorylation and dephosphorylation of proteins on tyrosyl residues are key regulatory mechanisms in T-cell signal transduction and are controlled by the opposing activities of protein tyrosine kinases and phosphotyrosyl phosphatases (PTPs). In T cells, several nontransmembrane protein tyrosine kinases are associated with receptors; for example, Lck is bound to the coreceptors CD4 and CD8 and becomes activated upon their stimulation. In comparison, little is known about the role of nontransmembrane PTPs in early T-cell signaling. SH-PTP1 (PTP1C, HCP, SHP) is a nontransmembrane PTP expressed primarily in hematopoietic cells, including T cells. We have found that SH-PTP1 is basally phosphorylated on serine in resting T cells. Upon stimulation of CD4 or CD8 either in a T-cell hybridoma cell line or in primary thymocytes, SH-PTP1 becomes tyrosyl phosphorylated. Moreover, SH-PTP1 is constitutively phosphorylated on tyrosine in the Lck-overexpressing lymphoma cell line LSTRA. SH-PTP1 is also a good substrate for recombinant Lck in vitro. Comparisons of the tryptic phosphopeptide maps of wild-type SH-PTP1 and deletion and point mutations establish that the two sites (Y-536 and Y-564) which are directly phosphorylated by Lck in vitro are also phosphorylated in vivo in LSTRA cells. One of these sites (Y-564) is phosphorylated in T cells in response to Lck activation. We conclude that SH-PTP1 undergoes Lck-dependent tyrosyl phosphorylation in T cells and likely plays a role in early T-cell signaling.     

Studies on the product of antigenic recognition. I. Formation of the product in recognition of alloantigens.

A product of antigenic recognition (PAR) was produced whenever receptors for alloantigens from T lymphocytes or a principle present in T-cell dependent alloantisera interacted with alloantigen. With two forms of the PAR assay (direct and indirect) the mechanisms underlying these interactions have been analyzed. For the interaction of T-lymphocyte receptors with alloantigen measured with direct PAR assays, the following conclusion emerged: upon confrontation with alloantigen, receptors (if not already present in secreted form) had first to be released from T-cell membranes. Shed T-cell receptors interacted with alloantigens by solubilizing them. Both processes could be prevented by fixing cells with formaldehyde. Release of T-cell receptors was temperature-dependent, solubilization of alloantigens was not. Because in mixed cell cultures receptors had first to be shed, this process was considerably slower and, in concordance with temperature dependence of receptor release, took place only at 37 degrees C. Titration of T lymphocytes with 'bound' receptors by the direct PAR test revealed that in the presence of excess alloantigen 10(2) T cells sufficed to give measurable responses. Supernates of parental strain lymphocytes containing numerous T-cell receptor specificities could be depleted of one of them. Alloantisera raised in presence of T helper cells ('T alloantisera') contained a principle capable of recognizing alloantigens, alloantisera incited in the absence of T helpers ('B alloantisera') did not. The recognizing principle appeared to be IgG. Like T-cell receptors, it was capable of solubilizing alloantigens form target cell membranes. B alloantisera lacked this capacity and their alloantigen-recognizing moiety was found to be monomeric IgM. The mode of interaction of this IgM with alloantigen most likely consisted in fixation to and shielding of antigen.     

Angiocentric T-cell lymphoma

SUMMARY: The CD20+ variant of angiocentric T-cell lymphoma is an unusual type of T-cell lymphomas that present cystic changes in organs because of ischaemic necroses. The purpose of this study was to describe a case of CD20+angiocentric T-cell lymphoma, discussing its clinical, histopathological and immunohistochemical features, to analyze its proliferation kinetics and to consider its possible relationship to the Epstein-Barr virus (EBV) to understand better the pathobiological nature of the disease. METHODS: The clinical, histopathological, immunohistochemical and single-cell DNA cytophotometric features of the case were analyzed. In addition in situ hybridization was performed to detect EBV. RESULTS: The 24 years old woman was admitted to our Institute because of pain in the abdominal region and weight loss. There were enlarged lymph nodes on the neck, and biopsy was done. Histological diagnosis: angiocentric T-cell lymphoma, CD20+ variant. CD3, CD43, CD45RA and CD45R0 antigens were positive in the atypic lymphoid cells of the tumour and in cells infiltrating the vascular wall. DNA index was 0.8589 (hypodiploid). Tumour cells in G1 phase: 47%, S phase: 45.4%, G2 phase: 7.6%. Combined chemotherapy was administered because of clinical stadium IV/B of malignant lymphoma (5 CHOP-Bleo, CEPP, CEP, CMVE treatment). The disease showed gradual progression and the patient died 14 months after the first symptoms had appeared. CONCLUSIONS: In the last 13 years there were 5 cases of angiocentric T-cell lymphoma at our Institute. The CD20+ variant is rare, its clinical symptoms are special, the prognosis is unfavourable. The cause why we demonstrate this case is to call attention to a new treatment for these patients by immunotherapy using monoclonal antibodies against CD20 antigen.     

Diltiazem inhibits transferrin receptor expression and causes G1 arrest in normal and neoplastic T cells.

Transferrin receptor expression is essential for the proliferation of both normal and malignant T cells. While transferrin receptor expression in normal T cells is tightly coupled to interleukin-2 receptor expression, transferrin receptor expression in malignant cells is usually constitutive and is released from this constraint. Temporally, the appearance of these membrane receptors is preceded by changes in the expression of the proto-oncogenes c-myc and c-myb. In addition, although an increase in the level of intracellular free calcium occurs early in the sequence of T-cell activation, the activation events dependent on this calcium flux have not been resolved. In the present study we report that diltiazem, an ion channel-blocking agent that inhibits calcium influx, arrested the growth in vitro of both normal and malignant human T cells in the G1 phase of the cell cycle. However, diltiazem did not inhibit the expression of c-myc or interleukin-2 receptor mRNA and protein in normal mitogen-activated T cells or the constitutive expression of c-myc and c-myb mRNA in malignant T cells (T acute lymphoblastic leukemia cells). In contrast, diltiazem prevented the induction of transferrin receptor (mRNA and protein) in normal T cells and caused a progressive loss of transferrin receptor (mRNA and protein) in malignant T cells. These data demonstrate that diltiazem can dissociate several growth-related processes normally occurring in G1 and thereby disrupt the biochemical cascade leading to cell proliferation.     

PD-1 modulates regulatory T cells and suppresses T-cell responses in HCV-associated lymphoma

T regulatory (T(R)) cells suppress T-cell responses that are critical in the development of chronic viral infection and associated malignancies. Programmed death-1 (PD-1) also has a pivotal role in regulation of T-cell functions during chronic viral infection. To examine the role of PD-1 pathway in regulating T(R)-cell functions that inhibit T-cell responses during virus-associated malignancy, T(R) cells were investigated in the setting of hepatitis C virus-associated lymphoma (HCV-L), non-HCV-associated lymphoma (non-HCV-L), HCV infection alone and healthy subjects (HS). Relatively high numbers of CD4(+)CD25(+) and CD8(+)CD25(+) T(R) cells, as well as high levels of PD-1 expressions on these T(R) cells were found in the peripheral blood of subjects with HCV-L compared with those from non-HCV-L or HCV alone or HS. T(R) cells from the HCV-L subjects were capable of suppressing the autogeneic lymphocyte response, and depletion of T(R) cells in peripheral blood mononuclear cells from HCV-L improved T-cell proliferation. Additionally, the suppressed T-cell activation and proliferation in HCV-L was partially restored by blocking the PD-1 pathway ex vivo, resulting in both a reduction in T(R)-cell number and the ability of T(R) to suppress the activity of effector T cells. This study suggests that the PD-1 pathway is involved in regulating T(R) cells that suppress T-cell functions in the setting of HCV-associated B-cell lymphoma.     

Hypothesis: the pathogenesis of AIDS. Activation of the T- and B-cell cascades

The hypothesis is presented that a human T-cell leukemia virus (HTLV) or a related agent produces a lytic response of T cells manifested by the acquired immune deficiency syndrome (AIDS) and a proliferative response represented by the adult leukemia/lymphoma (ATL) syndromes. The sequence or cascade of T-cell events following loss of T4 helper cells in AIDS includes reactivation of Epstein-Barr virus and a B-cell cascade of cytomegalovirus, resulting in Kaposi sarcoma in genetically susceptible persons, and of other intracellular agents (CNS viruses, M. avium intracellulari, T. gondii); opportunistic infections also occur. A comparison of AIDS and ATL syndromes is presented and the details of the B-cell cascade are outlined. The usefulness of prospective serological/immunological studies is discussed in an effort to determine the temporal sequence of infection by the candidate agents and their relation to the appearance of T4/T8 reversal and of the clinical features of AIDS.     

Antigen-specific murine T-cell lymphomas. II. H-2 restriction of primary and secondary responses

A stable clone of C57BL/6 (H-2b) radiation leukemia virus transformed ovalbumin (OVA)-specific murine T-cell lymphoma cells was able to mediate carrier-specific helper activity. The ability of these lymphoma cells to express helper activity for both primary and secondary hapten-specific B-cell responses was analyzed in nonirradiated normal or hapten-primed recipients. The lymphoma cells augmented anti-hapten responses in a carrier-specific manner; no bystander effects were noted. Helper activity was primarily noted in the IgG responses. The genetic restrictions affecting the expression of lymphoma-mediated helper activity were also analyzed. The pattern of restriction indicated that genes in the H-2 complex controlled the expression of helper activity; disparities at the Igh complex failed to influence helper activity. The cellular site of the H-2 restriction was between the antigen-presenting cells and the T-cell lymphoma not between the T and B cells. Precise intra-H-2 mapping of the gene(s) which control expression of lymphoma-mediated helper activity was attempted. Although most of the data were consistent with localization of the gene(s) to the I-A region, anomolous responses were noted in one strain.     

Cytologic features of NK/T-cell lymphoma

OBJECTIVE: To describe the diagnostic cytologic features of NK/T-cell lymphoma. STUDY DESIGN: The cytologic features of 3 cases of natural killer cell (NK)/T-cell lymphoma were studied and correlated with histology. Immunohistochemistry for CD56, T-cell intracellular antigen (TIA-1) and EBV-encoded small nuclear RNAs (EBER) in situ hybridization was reviewed. RESULTS: The lymphomas have mixed-sized cells with eccentric, round to ovoid nuclei; 1 or 2 prominent nucleoli; and abundant, clear to pale, eosinophilic cytoplasm. Mitotic figures, necrotic debris and tingible body macrophages are common accompaniments. In fluid, the lymphoma cells appear more shrunken. A clot section of 1 case was positive for CD56, TIA-1 and EBER. CONCLUSION: Helpful cytologic features for the diagnosis of NK/T-cell lymphoma are described. Immunohistochemistry for CD56, TIA-1 and EBER in situ hybridization are very helpful adjuncts for the diagnosis.     

FNAC of malignant lymphoma in an area with a high incidence of T-cell lymphoma. Correlation of accuracy of cytologic diagnosis with histologic subtype and immunophenotype

OBJECTIVE: To analyze the usefulness of fine needle aspiration cytology on malignant lymphoma in an area with a high incidence of T-cell lymphoma and to correlate the accuracy of cytologic diagnosis with histologic subtype and immunophenotype. STUDY DESIGN: We retrospectively studied the usefulness of fine needle aspiration cytology in the diagnosis of 49 cases of nodal and extranodal non-Hodgkin's lymphoma (NHL) and seven cases of Hodgkin's disease in a total of 56 patients in whom subsequent excisional biopsy revealed lymphoid malignancy. Slides showing the results of cytologic investigation were reviewed together with the information on which histologic diagnosis was based. On the basis of pathologic variables, such as prognostic groups based on the Working Formulation, so-called grade, cell size based on the modified Rappaport classification, and--in cases of NHL--immunophenotype, the accuracy of original and reviewed cytologic diagnoses was compared. RESULTS: Of the 49 cases of NHL, 8 (16.3%) were inadequate for cytologic diagnosis, and malignant lymphoma was diagnosed or suspected in 36 (73.5%), excluding inadequate specimens; the diagnostic accuracy for NHL was 87.8%. In high grade cases, malignant lymphoma was more easily diagnosed or suspected than in those that were low or intermediate grade. The rate of inadequate cases was highest in the "mixed small and large cell" category, and cases that were "false negative" were either composed entirely of small cells or contained a small cell component. Cytologic diagnosis or suspicion of malignant lymphoma was easily obtained in the "large cell" category, followed by mixed small and large cell and "small cell." Aspirates from non-B-cell type were more frequently acellular than those of B-cell type; with regard to diagnostic accuracy, however, there was no noticeable difference between the two immunophenotypes. CONCLUSION: In many cases in the mixed small and large cell category or where the immunophenotype was non-B, the aspirate was inadequate, and no definitive diagnosis was possible. Many of our cases of T-cell lymphoma were mixed small and large cell, and in Korea, where the incidence of extranodal and T-cell lymphoma is high, the usefulness of FNAC for the initial diagnosis of malignant lymphoma is limited. For a definitive diagnosis, biopsy is required.     

Fusion of T and B cells.

Hybrid cells were prepared by fusin an immunoglobulin-secreting mouse myeloma lin e (B cell) with an allogenic T-cell lymphoma which expresses the surface antigen Thy 1. The resulting hybrids expressed H2 antigens of both parental cells and secreted the immunoblobulin of the myeloma parent but did not express the Thy 1 antigen of the lymphoma parent. Twenty-one hybrids were formed from fusion of the same myeloma line with TNP-SRBC-primed spleen cells. Most of the hybrid lines exhibited characteristics expected for the fusion of the myeloma to B lymphocytes. No hybrids between the myeloma line and spleen T cells were identified as none of the hybrids expressed the T-cell-specific antigen Thy 1. We discuss possible reasons for failure to produce hybrids with T-cell characteristics in these types of fusion.     

Analysis of Tax-expressing cell lines generated from HTLV-I tax-transgenic mice: correlation between c-myc overexpression and neoplastic potential

Human T-cell leukemia/lymphotropic virus type I (HTLV-I) infection causes a variety of human diseases, including adult T-cell leukemia/lymphoma. The viral transactivator Tax has been implicated as a key factor in the HTLV-I-induced transformation pathway. To investigate the components of this pathway, we derived fibroblast-like cell lines, designated T6 and T9, from tail biopsies of tax-transgenic C57BL/6 mice that do not develop tumors. Phenotypic characterization of T6 and T9 cells and T6-derived subclones revealed that they differ in their abilities to form foci in vitro and tumors in vivo. The observed differences in the levels of Tax expression did not correlate with their degree of neoplastic potential. However, a control cell line derived from a nontransgenic C57BL/6 mouse did not form foci in vitro or tumors in vivo, indicating that Tax was required for the transformation process. Results of Northern analyses showed that the T9 cells and the highly malignant derivatives of T6 cells expressed elevated levels of c-myc mRNA. These findings suggest that progression of the tax-transgenic cells toward a more malignant phenotype might involve c-myc deregulation.     

Transplantation tolerance at the T-lymphocyte receptor level. II. Interaction of T-cell receptors with alloantigen and with anti-receptor antiserum.

CBA T lymphocytes deprived temporarily of receptors for alloantigens A[RS(A)] cultivated in vitro for 30 h with anti-receptor antibody-forming (AxCBA)F1 spleen cells were capable of resynthesizing RS(A) if primed F1 cells exceeded parental T cells by a factor of 25 or less, but not if the excess was 50-fold or more. This indicated that resynthesis of CBA T-cell RS(A) was successful if primed F1 cells formed insufficient amounts of anti-CBA T-cell RS(A) antibody. Abortive or successful receptor resynthesis was measured by two parameters, (a) reappearing RS(A) formed PAR together with A alloantigens of (AxCBA)F1 spleen cells and (b) budding receptors bound anti-receptor antibody. CBA B lymphocutes did not interfere with these reactions. A search for putative T suppressor cells in the F1 cell population was unsuccessful. PAR formation and anti--RS antibody consumption by reappearing receptors differed temporally: receptors forming PAR were present after a delay lasting 8 h; receptor structures fixed anti-RS antibody as early as 5 h after being cultivated. With due caution, these results might reflect processes operating in maintenance of transplantation tolerance, suggesting that this condition is a serum-mediated suppression of long duration. The suppression would encompass continued neutralisation of receptors for the alloantigen to be tolerated by anti-T-cell receptor antibody formed by the F1 chimeric cells within an animal with acquired transplantation tolerance.     

Mechanisms of Dihydroartemisinin and Dihydroartemisinin/Holotransferrin Cytotoxicity in T-Cell Lymphoma Cells

The validated therapeutic effects of dihydroartemisinin (DHA) in solid tumors have encouraged us to explore its potential in treating T-cell lymphoma. We found that Jurkat cells (a T-cell lyphoma cell line) were sensitive to DHA treatment with a IC50 of dihydroartemisinin. The cytotoxic effect of DHA in Jurkat cells showed a dose- and time- dependent manner. Interestingly, the cytotoxic effect of DHA was further enhanced by holotransferrin (HTF) due to the high expression of transferrin receptors in T-cell lymphoma. Mechanistically, DHA significantly increased the production of intracellular reactive oxygen species, which led to cell cycle arrest and apoptosis. The DHA treatment also inhibited the expression of protumorgenic factors including VEGF and telomerase catalytic subunit. Our results have proved the therapeutic effect of DHA in T-cell lymphoma. Especially in combination with HTF, DHA may provide a novel efficient approach in combating the deadly disease.     

Three classes of signalling molecules on B-cell membranes

The question of whether surface immunoglobulin and Ia molecules have a signalling function in helper T cell-dependent activation of B cells has been evaluated. Two sources of B cells have been used, one a purified population of hapten-binding B cells, the other a B-cell lymphoma, CH12, with known antigen specificity. Evidence is presented that both immunoglobulin and Ia molecules are receptors actively involved in the initial activation of resting B cells. Nevertheless, the requirements for ligand binding to either receptor can be bypassed under appropriate conditions, and the implications of this result for the function of these molecules is discussed. With respect to B-cell Ia, the authors present data that demonstrate two distinct functions of this molecule, one as a restricting element for T-cell activation, the second as a signalling receptor for B-cell excitation. On the CH12 surface, the I-A molecule fulfills the former function, but T-cell interactions with I-A fail to result in B-cell stimulation, suggesting that B-cell Ia may limit helper T cell-B cell interactions. We suggest that the binding of antigen surface immunoglobulin and binding of helper T-cell receptors to the appropriate Ia molecule(s) results in the activation of genes that encode for a third class of membrane B-cell receptors, those that bind B-cell stimulating factors.     

Circumventing T-cell tolerance to tumour antigens.

During past decades, many attempts have been made to induce or enhance tumour-specific T-cell immunity in cancer patients by vaccination. However, it has become apparent that in a large number of cases the naturally occurring tumour-specific T-cell repertoire is of low affinity and therefore inefficient in mediating tumour rejection. Because of the potential therapeutic value of high affinity TCRs with tumour/lineage specificities, we set out to develop a number of new technologies that can be used to create improved tumour-specific T-cell immunity. These strategies entail: (i) the efficient expansion of low affinity T cells specific for self antigens through the use of variant peptides with improved TCR-binding characteristics; (ii) a retroviral library-based technology to improve the affinity of (self-specific) T-cell receptors in vitro, and (iii) proof of principle for the feasibility of TCR gene transfer as a means to generate T-cell populations with a desired antigen-specificity in vivo. Collectively this toolbox should allow us to create improved T-cell receptors for human tumour antigens, which can subsequently be used to impose tumour-reactivity on to peripheral T cells.     

Modulation of chronic lymphocytic leukemia (CLL) lymphocyte phenotypes by in vitro incubation with alpha 1 thymosin

In this study an attempt was made to elucidate (1) the level(s) of differentiation arrest of B cells, and (2) whether T-cell functional defects in CLL patients are related to their defective maturation. In addition, an attempt was also made to induce and/or correct maturation of T cells in CLL patients by in vitro incubation with alpha 1 thymosin. In CLL patients and controls, we determined the percentage of T and B cells with T11, T8, T4, C3, and mouse erythrocyte (ME) receptors, along with T-cell functional reactivity (measured by local xenogeneic graft vs host reaction), before and after incubation with alpha 1 thymosin. In about 60% of stable CLL patients, and in 80% of those in the progressive phase of disease, T cells possess receptors for ME and/or C3. After incubation with alpha 1 thymosin, separate analysis of surface markers on T and B cells revealed (along with the induction of T11 receptors on T-cell surface) induction of ME receptors on T and B cells in stable phase and selective loss of ME receptors on B cells in the progressive phase of CLL. After incubation of normal lymphocytes with alpha 1 thymosin, we observed an increase of T8 receptors, no change in expression of T11, and a decrease of T4 receptors along with the increase of the intensity of T-cell functional reactivity. In contrast, in CLL patients following incubation with alpha 1 thymosin, the induction of T8 receptors was less prominent in the progressive than in the stable phase of disease. Furthermore, induction of T8 receptors in CLL patients in the stable phase was accompanied by recovery of impaired or increase of preserved functional T-cell reactivity. In the progressive phase, however, T-cell functional areactivity remained unchanged. The findings suggest that different levels of B-cell-differentiation arrest along with defective maturation of T cells might be responsible for the spectrum of disease evolution in CLL.     

DNAM-1 mediates epithelial cell-specific cytotoxicity of aberrant intraepithelial lymphocyte lines from refractory celiac disease type II patients

In refractory celiac disease (RCD), intestinal epithelial damage persists despite a gluten-free diet. Characteristic for RCD type II (RCD II) is the presence of aberrant surface TCR-CD3(-) intraepithelial lymphocytes (IELs) that can progressively replace normal IELs and eventually give rise to overt lymphoma. Therefore, RCD II is considered a malignant condition that forms an intermediate stage between celiac disease (CD) and overt lymphoma. We demonstrate in this study that surface TCR-CD3(-) IEL lines isolated from three RCD II patients preferentially lyse epithelial cell lines. FACS analysis revealed that DNAM-1 was strongly expressed on the three RCD cell lines, whereas other activating NK cell receptors were not expressed on all three RCD cell lines. Consistent with this finding, cytotoxicity of the RCD cell lines was mediated mainly by DNAM-1 with only a minor role for other activating NK cell receptors. Furthermore, enterocytes isolated from duodenal biopsies expressed DNAM-1 ligands and were lysed by the RCD cell lines ex vivo. Although DNAM-1 on CD8(+) T cells and NK cells is known to mediate lysis of tumor cells, this study provides, to our knowledge, the first evidence that (pre)malignant cells themselves can acquire the ability to lyse epithelial cells via DNAM-1. This study confirms previous work on epithelial lysis by RCD cell lines and identifies a novel mechanism that potentially contributes to the gluten-independent tissue damage in RCD II and RCD-associated lymphoma.     

Induction of antigen-specific effector-phase tolerance following vaccination against a previously ignored B-cell lymphoma

The mechanisms of immune evasion during haematological malignancies are poorly understood. As lymphomas grow in lymphoid organs, it would be expected that if these lymphomas express neo-antigens they should be readily detected by the immune system. To test this assumption, we generated a new non-Hodgkin B-cell lymphoma model expressing the model tumour neo-antigen Ovalbumin (OVA), and analysed the endogenous antigen-specific CD8(+) T-cell response that it elicited in recipient mice. The OVA+ lymphoma cells were eliminated by cytotoxic T lymphocytes (CTL) in mice that had been previously vaccinated against OVA. In contrast, the immune system of na?ve mice ignored the malignant cells even though these continuously expressed and presented OVA on their MHC class I molecules. This state of ignorance could be overcome by therapeutic vaccination, which led to the expansion of endogenous anti-OVA-specific CD8(+) T cells. However, the cytotoxic and interferon-γ secretion capacity of these T cells were impaired. The tumour model that we describe thus reproduces several key aspects of human lymphoma; tumor ignorance can be broken by vaccination but the ensuing immune response remains ineffective. This model can be exploited to further understand the mechanisms of lymphoma immunoevasion and devise effective immunotherapy.