scholarly journals Molecular Signatures of Immune Pressure and Immune Escape in Hematological Malignancies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1093-1093
Author(s):  
Simona Pagliuca ◽  
Carmelo Gurnari ◽  
Tariq Kewan ◽  
Waled Bahaj ◽  
Minako Mori ◽  
...  
Keyword(s):  
Immune Response ◽  
Somatic Mutations ◽  
Hematological Malignancies ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Q Value ◽  
Tumor Surveillance ◽  
Immune Pressure ◽  
Genomic Study

Abstract Downmodulation of antigen presentation machinery represents a paradigm of evasion from adaptive immune surveillance. This mechanism underpins the decrease in presentation of immunogenic peptides below the activation threshold of effector T-cells. Large genomic aberrations, fine somatic mutations, epigenetic silencing and transcriptional modifications involving directly the human leukocyte antigen (HLA) region or genes encompassing antigen degradation, transportation and processing have been invoked across large cohorts of solid tumors and hematological disorders, all as a result of a common lynchpin: the established immune pressure. During tumor growth this orchestra of mechanisms shape the oncogenic landscape and facilitate the emergence of clones with lower immunogenic potential. By analyzing genomic profiles extracted from more than 7000 patients and specimens across 25 previously published cohorts encompassing both lymphoid and myeloid diseases (Table 1), we performed a large genomic study aiming to dissect the multifaceted immunoediting processes in hematological malignancies We first analyzed a broad HLA genomic dysfunction in 31 classical and non-classical loci and identified 892 somatic mutations or allelic losses in 337/6694 patients (5%). Among the different subtypes of hematological malignancies, HLA mutations were found in 16% (N=138/831) of acute lymphoblastic leukemia (ALL), 7% (N=1/14) of histiocytic disorders, 7% (N=3/43) of T-cell lymphoma, 6% (N=136/2247) of myeloid disorders, 2% (N=4/205) of multiple myeloma, 1.6% (N=55/3354) of B-cell lymphoma/chronic lymphocytic leukemia (B-LNH/CLL). Most affected loci were classical A, B and DRB1, while non-classical DPB2, F and DOA were the least interested by somatic events. Interestingly, alterations were never found in non-expressed DRB genes (DRB2-4,7-9). Among the immune genes, we focused on those which, if affected by mutations (either loss or gain of function), could possibly be associated with an immune escape signature. We identified such aberrations in 13% of cases, including CREBBP (4.5%, N=450/9875), EP300 (2.5%, N=252/9831), IRF8 (2.1%, N=166/7865), B2M (2%, N=158/7868), CD70 (1.7%, N=127/7253), TNFRSF14 (2.8%, N=221/7868), IRF4 (1.4%, N=110/7869), which were the most frequently altered. The frequency of those mutations was particularly high in B-NHL/CLL (28%) and ALL (23%). These events and HLA hits were not mutually exclusive. When analyzing the pattern of co-mutations in immune aberrant vs. non-aberrant group, we found that both lymphoid and myeloid entities were enriched in genomic abnormalities also in other immune players (e.g., NOTCH4, NFKB1, IL4R, IFNAR2, C3), emphasizing how the genomic dysfunction of the immune response may be a pathophysiological link, beyond the disease ontogenic classification. Of note is that, in MN subset, aberrations in leukemic drivers, such as: NPM1 (3% vs 16%, q=4.69E-11), JAK2 (3% vs 9%, q=1.00E-04), FLT3 (7% vs 14%, q=1.26E-04), SRSF2 (4% vs 10%, q-value=2.20E-04), DNMT3A (13% vs 21%, q=.001), TP53 (6% vs 10%, q=.009), NRAS (7% vs 12%, q=.021) were enriched in the non-immune-altered group. When accounting for the total number of mutational events, we found that this was significantly increased in immune aberrant vs. non-aberrant cases (q-value=10e-10) in both lymphoid and myeloid disorders. These findings are consistent with the hypothesis that HLA and immune defective escaping clones may arise in the context of a strong anti-tumor response, as a negative feedback to the immunoediting responsible for sculpting the tumor clonal burden. While driver hits can easily gain a fitness advantage regardless of the acquisition of immune escape signatures, immune-aberrant clones (especially if lacking more strong leukemogenic hits) would accrue subclonal alterations as a result of evasion from tumor surveillance, promoting growth only when opposing immune response. In analogy with solid cancers, our results show that also in hematological malignancies, the biology underpinning immune escape mechanisms is intimately related to the processes of immunoediting and may shape malignant clonal progression. In this setting, mutations in determinants of immune responsiveness might constitute markers of operative tumor surveillance. Figure 1 Figure 1. Disclosures Maciejewski: Novartis: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.

scholarly journals Targeting the tumor microenvironment in B-cell lymphoma: challenges and opportunities

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yingyue Liu ◽  
Xiangxiang Zhou ◽  
Xin Wang
Keyword(s):  
Tumor Microenvironment ◽  
B Cell ◽  
Hematological Malignancies ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Clinical Value ◽  
Challenges And Opportunities ◽  
Biological Heterogeneity ◽  
Novel Therapeutic Strategies

AbstractB-cell lymphoma is a group of hematological malignancies with high clinical and biological heterogeneity. The pathogenesis of B-cell lymphoma involves a complex interaction between tumor cells and the tumor microenvironment (TME), which is composed of stromal cells and extracellular matrix. Although the roles of the TME have not been fully elucidated, accumulating evidence implies that TME is closely relevant to the origination, invasion and metastasis of B-cell lymphoma. Explorations of the TME provide distinctive insights for cancer therapy. Here, we epitomize the recent advances of TME in B-cell lymphoma and discuss its function in tumor progression and immune escape. In addition, the potential clinical value of targeting TME in B-cell lymphoma is highlighted, which is expected to pave the way for novel therapeutic strategies.

Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma

Cell ◽  
1986 ◽  
Vol 44 (1) ◽  
pp. 97-106 ◽  
Author(s):  
Michael L. Cleary ◽  
Timothy C. Meeker ◽  
Shoshana Levy ◽  
Elizabeth Lee ◽  
Martha Trela ◽  
...  
Keyword(s):  
B Cell ◽  
Heavy Chain ◽  
Somatic Mutations ◽  
Cell Lymphoma ◽  
Variable Region ◽  
B Cell Lymphoma ◽  
Chain Gene ◽  
Heavy Chain Gene ◽  
Immunoglobulin Heavy Chain Gene ◽  
Human B Cell

Distinct roles for PARP-1 and PARP-2 in c-Myc-driven B-cell lymphoma in mice

Blood ◽  
2021 ◽  
Author(s):  
Miguel A Galindo-Campos ◽  
Nura Lutfi ◽  
Sarah Bonnin ◽  
Carlos Martínez ◽  
Talia Velasco-Hernandez ◽  
...  
Keyword(s):  
Dna Damage ◽  
B Cells ◽  
B Cell ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
Tumour Progression ◽  
Cancer Therapeutics ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Parp 1

Dysregulation of the c-Myc oncogene occurs in a wide variety of haematologic malignancies and its overexpression has been linked with aggressive tumour progression. Here, we show that Poly (ADP-ribose) polymerase (PARP)-1 and PARP-2 exert opposing influences on progression of c-Myc-driven B-cell lymphomas. PARP-1 and PARP-2 catalyse the synthesis and transfer of ADP-ribose units onto amino acid residues of acceptor proteins in response to DNA-strand breaks, playing a central role in the response to DNA damage. Accordingly, PARP inhibitors have emerged as promising new cancer therapeutics. However, the inhibitors currently available for clinical use are not able to discriminate between individual PARP proteins. We found that genetic deletion of PARP-2 prevents c-Myc-driven B-cell lymphomas, while PARP-1-deficiency accelerates lymphomagenesis in the Em-Myc mouse model of aggressive B-cell lymphoma. Loss of PARP-2 aggravates replication stress in pre-leukemic Em-Myc B cells resulting in accumulation of DNA damage and concomitant cell death that restricts the c-Myc-driven expansion of B cells, thereby providing protection against B-cell lymphoma. In contrast, PARP-1-deficiency induces a proinflammatory response, and an increase in regulatory T cells likely contributing to immune escape of B-cell lymphomas, resulting in an acceleration of lymphomagenesis. These findings pinpoint specific functions for PARP-1 and PARP-2 in c-Myc-driven lymphomagenesis with antagonistic consequences that may help inform the design of new PARP-centred therapeutic strategies with selective PARP-2 inhibition potentially representing a new therapeutic approach for the treatment of c-Myc-driven tumours.

Abstract B14: Natural killer immune response is promoted by the treatment of B-cell lymphoma cancer cells with membrane ionophores

2020 ◽  
Author(s):  
Abdessamad Zerrouqi ◽  
Anna Torun ◽  
Nina Miazek ◽  
Zofia Pilch ◽  
Jakub Golab ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Cancer Cells ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

scholarly journals PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell–inflamed phenotype

Blood ◽  
2019 ◽  
Vol 133 (21) ◽  
pp. 2279-2290 ◽  
Author(s):  
James Godfrey ◽  
Sravya Tumuluru ◽  
Riyue Bao ◽  
Michael Leukam ◽  
Girish Venkataraman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Immune Escape ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Data Set ◽  
Large B Cell Lymphoma ◽  
Programmed Death ◽  
Large B Cell ◽  
Gene Alterations

Abstract Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

Generation of CD8 T Cell-Mediated Protective Immunity against Tumor Escapees

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2623-2623 ◽  
Author(s):  
Bindu Varghese ◽  
Behnaz Taidi ◽  
Adam Widman ◽  
James Do ◽  
R. Levy
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Ex Vivo ◽  
B Cell Lymphoma ◽  
Cd8 T Cell

Abstract Introduction: Anti-idiotype antibodies against B cell lymphoma have shown remarkable success in causing tumor regression in the clinic. In addition to their known ability to mediate ADCC, anti-idiotype antibodies have also been shown to directly inhibit the proliferation of tumor cells by sending negative growth signals via the target idiotype. However, further studies to investigate this mechanism have been hindered by the failure of patient tumor cells to grow ex vivo. Methods and Results: In order to study this phenomenon further, we developed an antibody against the idiotype on an A20 mouse B lymphoma cell line. A radioactive thymidine incorporation assay showed decreased A20 cell proliferation in the presence of the anti-id antibody ex vivo. In vivo, when mice were treated intraperitoneally (i.p.) with 100 μg of antibody 3 hours post-tumor inoculation (1×106 A20 subcutaneously (s.c.)), tumor growth was delayed for greater than 40 days after which the tumor began to grow once again. Further analysis of these escaping tumor cells by flow cytometry showed that that the tumor cells escaped the antibody-mediated immune response by down-regulating expression of idiotype and IgG on their surfaces although the cells retained idiotype expression intracellularly. This down-regulation of surface idiotype rendered the tumor cells resistant to both ADCC and signaling-induced cell death. The addition of an immunostimulatory bacterial mimic (CpG-DNA; 100 μg × 5 intratumoral (i.t.) injections; Days 2, 3 4, 6 & 8) to antibody therapy (Day 0; 100 μg i.p.) cured large established tumors (Day 0 = 1 cm2) and prevented the occurrence of tumor escapees (p<0.0001). Antibody plus CpG combination therapy in tumor-bearing mice deficient for CD8+ T cells demonstrated the critical role of CD8+ T cells in A20 tumor eradication (p<0.005). Depletion of CD4+ T cells was found to have no significant impact on the therapy. We also found that when mice were inoculated with two tumors and treated with anti-idiotype antibody (i.p.) followed by intratumoral CpG in just one tumor (Day 0=1 cm2; anti-idiotype antibody 100 μg Day 0; 100 μg CpG Days 2, 3, 4, 6 & 8), untreated tumors regressed just as well as CpG-treated tumors indicating a systemic anti-tumor immune response was generated. Conclusion: Anti-idiotype therapy, although effective in delaying tumor growth, frequently generates antigen-loss variants. However, we found that when anti-idiotype antibodies were combined with CpG, even large established tumors were cured due to systemic CD8+ T cell-dependent tumor immunity. Rather than simply mediating ADCC against a single tumor antigen, which requires the constant infusion of antibody to hamper tumor growth, we hypothesize a cytotoxic T-cell response against many tumor antigens was also generated. Such a diverse T-cell repertoire can prevent the emergence of tumor escapees and collectively provide long-lasting tumor protection. These pre-clinical results suggest that anti-tumor antibodies combined with CpG warrant further study in patients with B cell lymphoma.

Epigenetic Inactivation of DBC1 in Acute Myeloid Leukaemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4429-4429
Author(s):  
Chen Zhao ◽  
Aili Dai ◽  
Ling Chen ◽  
Xiaoping Sun ◽  
Xin Han ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hematological Malignancies ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Acute Myeloid

Abstract Abstract 4429 DNA hypermethylation has important implications in the tumorigenesis and prognosis in acute myeloid leukemia (AML). To identify relevant methylated genes in AML, we have compared several expression and methylation profilings. With expression analysis, we identified that TRPC6, DBC1, DCC and SOX9 have decreased expression levels in the most analyzed AML cell lines. Among these candidates, DBC1 (deleted bladder cancer 1), a putative tumor suppressor, drew our attention because it is frequently methylated not only in hematological malignancies, including diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and acute lymphoblastic leukemia, but also in epithelial cancers. DBC1 may play an important role in the regulation of cell growth and programmed cell death. But the mechanisms of transcriptional control and function role in the hematological malignancies, especially on acute myeloid leukemia, are not well known. In this study, we analyzed the DBC1 expression pattern in 9 AML cell lines with RT-PCR analysis. DBC1 mRNA expression was observed in normal bone-marrow but diminished expression in all of 9 AML cell lines. DBC1 methylation was frequently observed in AML cells (9 of 9, 100%) and inversely correlated with DBC1 mRNA expression in a COBRA analysis (Combined Bisulfite Restriction Analysis). We also detected a frequent methylation of DBC1 in primary AML patient samples (9 of 9, 100%). These findings indicate that DBC1 is frequently silenced by hypermethylation in AML. We are in the process of investigation the functional role of DBC1 in the pathogenesis. In addition, diagnostic and prognostic values of DBC1 in AML are being pursued.* Chen Zhao and Aili Dai contributed equally to the presented work. Disclosures: No relevant conflicts of interest to declare.

Gene Expression Signature of Host Immune Response Is Predictive of Follicular Lymphoma Patient Survival in Independent Cohorts, and Correlates with Transformation to Diffuse Large B-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2951-2951
Author(s):  
Ash A Alizadeh ◽  
Andrew J Gentles ◽  
Sylvia K Plevritis ◽  
Ronald Levy
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell ◽  
Independent Cohort

Abstract Abstract 2951 Poster Board II-927 Background: Expression signatures of infiltrating immune cells [1] have been shown to predict survival in follicular lymphoma (FL), but have not been cross-validated in independent patient cohorts [2,3]. These signatures may relate biologically to the frequency of infiltrating including T-cells and macrophages, or to specific transcription programs within tumor cells and/or the tumor microenvironment. We sought to evaluate the validity of this model in an independent cohort of patients with FL, assessing its relationship to outcomes including histological transformation and death. Methods: The immune response (IR) predictor score proposed by Dave et al. [1] was applied to gene expression data from an independent cohort of 88 FL patients [4] with known survival outcomes and history of transformation to diffuse large B-cell lymphoma (DLBCL). Genes (n=66) corresponding to IR1 and IR2 signatures were mapped from Affymetrix microarrays [1] to a custom cDNA array [4] via Entrez Gene ID, and the composite IR score was calculated per the scheme proposed by Dave et al. Results: The IR score was predictive of patient outcome in the 88 patient test set as a continuous variable (p=0.001, HR=2.01, 95% CI 0.50-1.30). Partitioning of patients into high and low risk groups based on the median IR score across the cohort robustly separated survival curves (Figure A). The IR score was significantly higher in FL patients known to undergo transformation to DLBCL (Figure B: mean IR score of -0.6 in non-transforming FL vs. -0.2 in transforming FL; p∼10-11, t-test). Conclusions: The IR score of Dave et al. was highly significant as a predictor of survival in the independent patient cohort [4]. Moreover, the score was significantly associated with propensity of FL to transform to DLBCL. To our knowledge, immune cell infiltration has not previously been implicated in transformation. 1. Dave SS et al. (2004) Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351(21): 2159-2169. 2. Tibshirani R (2005) Immune signatures in follicular lymphoma. N Engl J Med 352: 1496-1497. 3. Chu G Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497. 4. Glas AM et al. (2005) Gene expression profiling in follicular lymphoma to assess clinical aggressiveness and to guide the choice of treatment. Blood 105(1): 301-307. Disclosures: No relevant conflicts of interest to declare.

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