PD-L1 expressed on tumor cells contributes to disease progression with evasion from tumor immunity. Plasma cells from multiple myeloma (MM) patients expressed higher levels of PD-L1 compared with ...healthy volunteers and monoclonal gammopathy of undetermined significance (MGUS) patients, and its expression is significantly upregulated in relapsed/refractory patients. Furthermore, high PD-L1 expression is induced by the myeloma microenvironment and PD-L1
patients with MGUS and asymptomatic MM tend to show disease progression. PD-L1 expression on myeloma cells was associated with more proliferative potential and resistance to antimyeloma agents because of activation of the Akt pathway through PD-1-bound PD-L1 in MM cells. Those data suggest that PD-L1 plays a crucial role in the disease progression of MM.
Background
Multiple myeloma (MM) is an incurable hematological malignancy. Despite the introduction of several novel drugs, most patients relapse. Biomarkers to identify the early signs of relapse ...will make it possible to adjust the therapeutic strategy before the disease worsens. Although understanding genetic changes is important for the treatment of MM, currently known biomarkers of relapse, including serum free-light chains and monoclonal paraproteins, are not associated with genetic changes.
Methods
We therefore performed a multicenter study to examine the usefulness of circulating cell-free DNA (cfDNA) present in the peripheral blood (PB) plasma of patients as a biomarker for MM relapse.
Results
We identified several driver mutations by combined analysis of next-generation sequencing and existing databases of candidate oncogenes. Furthermore, relapse was detected more sensitively by monitoring the circulating cfDNA with these driver mutations than by conventional serum free-light chain examination.
Conclusion
These results suggest the potential utility of cfDNA in the PB plasma of patients as a relevant early biomarker for MM relapse.
The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM ...family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing's sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention.
Despite the advent of novel therapies and improvements in survival, multiple myeloma (MM) remains an incurable disease. Thus, new treatment strategies including immunotherapies are needed for MM ...patients with stable disease after induction chemotherapy as well as for disease control in patients with advanced disease. However, profound immune dysregulation not only of B cells, but also of other immune cells such as natural killer cells, T cells, and dendritic cells and increase in the number of immunosuppressive cells, i.e., regulatory T and B cells and myeloid-derived suppressor cells, have been demonstrated in advanced MM patients, which may be involved in disease progression. Because of immune dysfunction, immunotherapies have not shown clinical efficacy in MM patients. It is therefore crucial to resolve immunosuppressive mechanisms and improve immune responses, especially in advanced MM patients. Recently, excellent clinical efficacy of new immunotherapeutic strategies such as immunomodulatory drug-intensified monoclonal antibody treatment, immune checkpoint inhibitors, and chimeric antigen receptor T-cell therapy targeting B cell maturation antigen has been reported in advanced-stage MM patients. Those new treatments or their combination will improve prognosis and possibly point toward a cure for myeloma.
Immunotherapy for Multiple Myeloma Tamura, Hideto; Ishibashi, Mariko; Sunakawa, Mika ...
Cancers,
12/2019, Volume:
11, Issue:
12
Journal Article
Peer reviewed
Open access
Despite therapeutic advances over the past decades, multiple myeloma (MM) remains a largely incurable disease with poor prognosis in high-risk patients, and thus new treatment strategies are needed ...to achieve treatment breakthroughs. MM represents various forms of impaired immune surveillance characterized by not only disrupted antibody production but also immune dysfunction of T, natural killer cells, and dendritic cells, although immunotherapeutic interventions such as allogeneic stem-cell transplantation and dendritic cell-based tumor vaccines were reported to prolong survival in limited populations of MM patients. Recently, epoch-making immunotherapies, i.e., immunomodulatory drug-intensified monoclonal antibodies, such as daratumumab combined with lenalidomide and chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, have been developed, and was shown to improve prognosis even in advanced-stage MM patients. Clinical trials using other antibody-based treatments, such as antibody drug-conjugate and bispecific antigen-directed CD3 T-cell engager targeting, are ongoing. The manipulation of anergic T-cells by checkpoint inhibitors, including an anti-T-cell immunoglobulin and ITIM domains (TIGIT) antibody, also has the potential to prolong survival times. Those new treatments or their combination will improve prognosis and possibly point toward a cure for MM.
Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic ...cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.
Background: Primary thyroid lymphoma (PTL) is a rare disease frequently arising against a background of autoimmune thyroiditis. It has recently been reported that the inactivation of the NF-κB ...negative regulator A20 by deletion and/or mutation could be involved in the pathogenesis of subsets of B-cell lymphomas. This study investigated the clinicopathologic characteristics and A20 mutation in patients with PTL. Methods: We analyzed the characteristics of 45 PTL patients (14 men and 31 women), with a median age of 71 (range, 35-90) years. A20 mutations were analyzed in DNA extracted from 20 samples consisting of 19 tumor tissue samples and 1 sample from Hashimoto's thyroiditis. Results: Thirty-five patients (82%) had a history of Hashimoto's thyroiditis, and 29 (64%) had diffuse large B-cell lymphoma (DLBCL) and presented with larger tumors including bulky mass, elevated soluble interleukin-2 receptor levels, and a longer history of Hashimoto's thyroiditis than that of patients with mucosa-associated lymphoid tissue (MALT) lymphoma (n=16). A20 mutations were identified in 3 of 19 PTL patients (16%), in 2 of the 10 (20%) with DLBCL and in 1 of the 9 (11%) with MALT lymphoma. Interestingly, all patients with A20 mutations had Hashimoto's thyroiditis. Furthermore, they had a common missense variant in exon 3 (rs2230926 380T>G; F127C), which reduces the ability of A20 to inhibit NF-κB signaling. Conclusion: Our study suggests that the histological features of PTL affect clinical outcomes and that A20 mutations are related to PTL pathogenesis in some patients with Hashimoto's thyroiditis.
Cancer immunotherapies including immune checkpoint inhibitor and cell-based regimens such as chimeric antigen receptor T cell therapy have progressed markedly in the last decade. However, the ...efficacy of those cancer immunotherapies is still limited in some patient populations due to the many mechanisms of antitumor immunomodulation, including immune checkpoint molecules expressed by both tumor cells and the tumor microenvironment, immunosuppressive cells, and tumor cell-derived factors such as extracellular vesicles. In this PIH review series, we focus on new knowledge and strategies to improve immunotherapies for cancer patients.
Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been ...reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among other immune checkpoints on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory; however, the mechanism by which changes in CD155 and CD112 expression affect tumor immunity remains unclear. When the increased expression of CD155 and CD112 activates Raf-MEK-ERK pathway and Raf-MEK-ERK pathway is one of the targets of FMS-like tyrosine kinase 3 (FLT3) inhibition. The present study investigated the alterations in CD155 and CD112 expression under FLT3 inhibition (quizartinib and gilteritinib) and studied its effect on NK and T cell cytotoxicity. CD155 and CD112 expression was analyzed using flow cytometry and reverse transcription-quantitative PCR in AML cell lines with or without FLT3 mutation using FLT3 inhibitors. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3-mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity against these cells by NK cells were enhanced. However, the cytotoxicity of γδ T cells with low TIGIT expression compared with NK cells was not enhanced in direct cytotoxicity assay using luciferase luminescence. The analysis of clinical trials from The Cancer Genome Atlas (TCGA) revealed that high CD155 and CD112 expression is associated with poor overall survival. The enhanced cytotoxicity of NK cells against CD155- and CD112-downregulated cells following FLT3 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using FLT3 inhibitors.
Contemporary approaches for vaccination and immunotherapy are often capable of eliciting strong T-cell responses against tumor antigens. However, such responses are not parallel to clinical tumor ...regression. The development of evasion mechanisms within tumor microenvironment may be responsible for poor therapeutic responses. We report here that constitutive or inducible expression of B7-H1, a B7 family molecule widely expressed by cancers, confers resistance to therapeutic anti-CD137 antibody in mice with established tumors. The resistance is accompanied with failure of antigen-specific CD8+ CTLs to destroy tumor cells without impairment of CTL function. Blockade of B7-H1 or PD-1 by specific monoclonal antibodies could reverse this resistance and profoundly enhance therapeutic efficacy. Our findings support that B7-H1/PD-1 forms a molecular shield to prevent destruction by CTLs and implicate new approaches for immunotherapy of human cancers.
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