C-C Chemokine Receptor 7 in Cancer.
Cells
C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers.
10.3390/cells11040656
Immunotherapy for Diffuse Large B-Cell Lymphoma: Current Landscape and Future Directions.
Modi Dipenkumar,Potugari Bindu,Uberti Joseph
Cancers
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. B-cell receptor (BCR) pathway is essential for malignant B-cell growth, survival, and proliferation. Various immune cells, including T-cells and macrophages in the tumor microenvironment (TME) contribute to tumor cell survival and pathogenesis of chemo-resistance. The presence of many targets on the malignant B-cells and in the TME has led to emergence of novel therapeutic agents. Stem cell transplant is the oldest treatment modality leveraging immune system in DLBCL. Subsequently, CD20 targeting monoclonal antibody and chimeric antigen receptor (CAR) T-cell therapy changed the treatment landscape of DLBCL. Recently, multiple novel immunotherapeutic agents have been added in the armamentarium for the management of DLBCL, and many are under development. In this review article, we will review latest updates of immunotherapeutic agents in the management of DLBCL.
10.3390/cancers13225827
Clinical Impact of Immune Cells and Their Spatial Interactions in Diffuse Large B-Cell Lymphoma Microenvironment.
Clinical cancer research : an official journal of the American Association for Cancer Research
PURPOSE:Tumor-infiltrating immune cells have prognostic significance and are attractive therapeutic targets. Yet, the clinical significance of their spatial organization and phenotype in diffuse large B-cell lymphoma (DLBCL) is unclear. EXPERIMENTAL DESIGN:We characterized T cells, macrophages, and their spatial interactions by multiplex IHC (mIHC) in 178 patients with DLBCL and correlated the data with patient demographics and survival. We validated the findings on gene expression data from two external DLBCL cohorts comprising 633 patients. RESULTS:Macrophage and T-cell contents divided the samples into T cell-inflamed (60%) and noninflamed (40%) subgroups. The T cell-inflamed lymphoma microenvironment (LME) was also rich in other immune cells, defining immune hot phenotype, which did not as such correlate with outcome. However, when we divided the patients according to T-cell and macrophage contents, LME characterized by high T-cell/low macrophage content or a corresponding gene signature was associated with superior survival [5-year overall survival (OS): 92.3% vs. 74.4%, P = 0.036; 5-year progression-free survival (PFS): 92.6% vs. 69.8%, P = 0.012]. High proportion of PD-L1- and TIM3-expressing CD163- macrophages in the T cell-inflamed LME defined a group of patients with poor outcome [OS: HR = 3.22, 95% confidence interval (CI), 1.63-6.37, Padj = 0.011; PFS: HR = 2.76, 95% CI, 1.44-5.28, Padj = 0.016]. Furthermore, PD-L1 and PD-1 were enriched on macrophages interacting with T cells. CONCLUSIONS:Our data demonstrate that the interplay between macrophages and T cells in the DLBCL LME is immune checkpoint dependent and clinically meaningful.
10.1158/1078-0432.CCR-21-3140
Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma.
Autio Matias,Leivonen Suvi-Katri,Brück Oscar,Mustjoki Satu,Mészáros Jørgensen Judit,Karjalainen-Lindsberg Marja-Liisa,Beiske Klaus,Holte Harald,Pellinen Teijo,Leppä Sirpa
Haematologica
The tumor microenvironment (TME) and limited immune surveillanceplay important roles in lymphoma pathogenesis. Here weaimed to characterize immunological profiles of diffuse large B-celllymphoma (DLBCL) and predict the outcome in response toimmunochemotherapy. We profiled the expression of 730 immune-relatedgenes in tumor tissues of 81 patients with DLBCL utilizing the Nanostringplatform, and used multiplex immunohistochemistry to characterize T-cellphenotypes, including cytotoxic T cells (CD8, Granzyme B, OX40, Ki67),T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well asregulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188patients. We observed a high degree of heterogeneity at the transcriptomelevel. Correlation matrix analysis identified gene expression signatureswith highly correlating genes, the main cluster containing genes for cytolyticfactors, immune checkpoint molecules, T cells and macrophages, togethernamed a TME immune cell signature. Immunophenotyping of the distinctcell subsets revealed that a high proportion of immune checkpoint positiveT cells translated to unfavorable survival. Together, our results demonstratethat the immunological profile of DLBCL TME is heterogeneous and clinicallymeaningful. This highlights the potential impact of T-cell immunecheckpoint in regulating survival and resistance to immunochemotherapy.(Registered at clinicaltrials.gov identifiers: NCT01502982 and NCT01325194.)
10.3324/haematol.2019.243626
A single-cell atlas of diffuse large B cell lymphoma.
Cell reports
Diffuse large B cell lymphoma (DLBCL) is one of the most common yet aggressive types of B cell lymphoma and remains incurable in 40% of patients. Herein, we profile the transcriptomes of 94,324 cells from 17 DLBCLs and 3 control samples using single-cell RNA sequencing. Altogether, 73 gene expression programs are identified in malignant cells, demonstrating high intra- and intertumor heterogeneity. Furthermore, 2,754 pairs of suggestive cell-cell interactions are predicted, indicating a complex and highly dynamic tumor microenvironment. Especially for B cell lymphomas, a strong costimulatory CD70-CD27 interaction is predicted between malignant and T cells. Furthermore, coinhibitory signals mediated by TIM3 or TIGIT seem to be the main driving force for T cell exhaustion. Finally, we find that chronic hepatitis B virus infection may have a significant impact on tumor cell survival and immune evasion in DLBCL. Our results provide insights into B cell lymphomagenesis and may facilitate the design of targeted immunotherapy strategies.
10.1016/j.celrep.2022.110713
Correlation between circulating blood and microenvironment T lymphocytes in diffuse large B-cell lymphomas.
Journal of clinical pathology
AIMS:Diffuse large B-cell lymphoma (DLBCL) is characterised by marked clinical and biological heterogeneity, attributable to the tumour cells and their microenvironment. METHODS:In this study, we investigated circulating subsets of blood lymphocytes and monocytes and their relationship with T cells in the tumour microenvironment (TME) in chemoresistant and chemosensitive patients with DLBCL. RESULTS:The study showed that (1) absolute lymphocyte count (ALC) and CD3+ and CD4+ cells were reduced in chemoresistant patients compared with chemosensitive patients; (2) lymphocyte:monocyte ratio (LMR) showed a positive correlation with peripheral blood CD3+ and CD4+ cells; (3) ALC, LMR, peripheral blood CD3+ and CD4+ cells showed a positive correlation with T cells in the TME. CONCLUSIONS:Overall, these data suggest that DLBCL with high TME T cells display a pre-existing antitumour immune response. In the rituximab-containing regimen, TME T cells are stimulated further to participate in the immune response against lymphoma cells. In contrast, DLBCL lymphomas with low T-cell infiltration reflect the absence of a pre-existing antitumour immunity and have a lower likelihood of obtaining an optimal response to therapy.
10.1136/jclinpath-2020-207048
IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.
Science advances
The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.
10.1126/sciadv.adk2091
IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHC CII complexes.
bioRxiv : the preprint server for biology
In diffuse large B-cell lymphoma (DLBCL), the transcription factor IRF8 is the target of a series of potentially oncogenic events, including, chromosomal translocation, focal amplification, and super-enhancer perturbations. IRF8 is also frequently mutant in DLBCL, but how these variants contribute to lymphomagenesis is unknown. We modeled IRF8 mutations in DLBCL and found that they did not meaningfully impact cell fitness. Instead, IRF8 mutants, mapping either to the DNA-binding domain (DBD) or c-terminal tail, displayed diminished transcription activity towards CIITA, a direct IRF8 target. In primary DLBCL, IRF8 mutations were mutually exclusive with mutations in genes involved in antigen presentation. Concordantly, expression of IRF8 mutants in murine B cell lymphomas uniformly suppressed CD4, but not CD8, activation elicited by antigen presentation. Unexpectedly, IRF8 mutation did not modify MHC CII expression on the cell surface, rather it downmodulated CD74 and HLA- DM, intracellular regulators of antigen peptide processing/loading in the MHC CII complex. These changes were functionally relevant as, in comparison to IRF8 WT, mice harboring IRF8 mutant lymphomas displayed a significantly higher tumor burden, in association with a substantial remodeling of the tumor microenvironment (TME), typified by depletion of CD4, CD8, Th1 and NK cells, and increase in T-regs and Tfh cells. Importantly, the clinical and immune phenotypes of IRF8-mutant lymphomas were rescued in vivo by ectopic expression of CD74. Deconvolution of bulk RNAseq data from primary human DLBCL recapitulated part of the immune remodeling detected in mice and pointed to depletion of dendritic cells as another feature of IRF8 mutant TME. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.
10.1101/2023.10.14.560755
Monitoring of Circulating Tumor DNA Improves Early Relapse Detection After Axicabtagene Ciloleucel Infusion in Large B-Cell Lymphoma: Results of a Prospective Multi-Institutional Trial.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
PURPOSE:Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. METHODS:Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel-related toxicity. RESULTS:A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell-associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( < .0001) and 19 months versus not reached ( = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. CONCLUSION:Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.
10.1200/JCO.21.00377
Determinants of resistance to engineered T cell therapies targeting CD19 in large B cell lymphomas.
Cancer cell
Most relapsed/refractory large B cell lymphoma (r/rLBCL) patients receiving anti-CD19 chimeric antigen receptor (CAR19) T cells relapse. To characterize determinants of resistance, we profiled over 700 longitudinal specimens from two independent cohorts (n = 65 and n = 73) of r/rLBCL patients treated with axicabtagene ciloleucel. A method for simultaneous profiling of circulating tumor DNA (ctDNA), cell-free CAR19 (cfCAR19) retroviral fragments, and cell-free T cell receptor rearrangements (cfTCR) enabled integration of tumor and both engineered and non-engineered T cell effector-mediated factors for assessing treatment failure and predicting outcomes. Alterations in multiple classes of genes are associated with resistance, including B cell identity (PAX5 and IRF8), immune checkpoints (CD274), and those affecting the microenvironment (TMEM30A). Somatic tumor alterations affect CAR19 therapy at multiple levels, including CAR19 T cell expansion, persistence, and tumor microenvironment. Further, CAR19 T cells play a reciprocal role in shaping tumor genotype and phenotype. We envision these findings will facilitate improved chimeric antigen receptor (CAR) T cells and personalized therapeutic approaches.
10.1016/j.ccell.2022.12.005