Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.

The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.

Real-world safety and effectiveness of tenofovir alafenamide for 144 weeks in Japanese patients with chronic hepatitis B.

Tenofovir alafenamide (TAF), a prodrug of tenofovir, delivers high levels of active drug to hepatocytes and is given in a lower dose than tenofovir disoproxil fumarate (TDF). TAF reduces viral replication in patients with chronic hepatitis B (CHB) similar to TDF and has shown a lower risk of the renal and bone toxicities associated with TDF use. This post-marketing surveillance study examined the safety and effectiveness of TAF in treatment-naïve and -experienced CHB patients who received TAF for 144 weeks at real-world clinical sites in Japan. Safety assessments included the incidence of adverse drug reactions (ADRs), renal and bone events, and changes in selected laboratory parameters. Effectiveness was based on the proportion of patients with HBV DNA levels below the lower limit of quantitation or <29 IU/mL. This analysis included 580 patients; 18.4% of whom were treatment-naïve. The cumulative incidence of ADRs was 0.21 per 100 person-months, and the incidence of serious ADRs was 0.01 (95% CI, 0.00-0.04) per 100 person-months. There were no ADRs of declines in estimated glomerular filtration rates, renal failure or proximal tubulopathy. The most common ADR was hypophosphataemia in seven (1.2%) patients. Two (0.4%) patients each had decreased blood phosphorus, bone mineral density decreased, dizziness and alopecia. Overall, the proportion of virologically suppressed patients increased from 68.8% at baseline to 97.5% at Week 144. These results confirm the real-world safety and effectiveness of TAF in Japanese patients with CHB and are consistent with the findings of other evaluations of the safety and efficacy of TAF in CHB.

TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance.

Phagocytosis of apoptotic cells by myeloid cells has been implicated in the maintenance of immune homeostasis. In this study, we found that T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM-4) repressed tumor-specific immunity triggered by chemotherapy-induced tumor cell death. TIM-4 was found to be highly expressed on tumor-associated myeloid cells such as macrophages (TAMs) and dendritic cells (TADCs) and danger-associated molecular patterns (DAMPs) released from chemotherapy-damaged tumor cells induced TIM-4 on tumor-associated myeloid cells recruited from bone marrow-derived precursors. TIM-4 directly interacted with AMPKα1 and activated autophagy-mediated degradation of ingested tumors, leading to reduced antigen presentation and impaired CTL responses. Consistently, blockade of the TIM-4-AMPKα1-autophagy pathway augmented the antitumor effect of chemotherapeutics by enhancing tumor-specific CTL responses. Our finding provides insight into the immune tolerance mediated by phagocytosis of dying cells, and targeting of the TIM-4-AMPKα1 interaction constitutes a unique strategy for augmenting antitumor immunity and improving cancer chemotherapy.

Real-world treatment patterns and clinical outcomes of Japanese patients with non-muscle invasive bladder cancer receiving intravesical bacillus Calmette-Guérin treatment.

OBJECTIVES: To investigate current patterns and outcomes of intravesical bacillus Calmette-Guérin treatment in Japanese patients with bladder cancer, including the proportion of patients completing induction therapy, and time to subsequent treatments. METHODS: This retrospective cohort study utilized administrative claims data from the Medical Data Vision Co., Ltd. database to identify patients with a diagnosis of bladder cancer who had received ≥1 prescription of intravesical bacillus Calmette-Guérin between April 2008 and September 2015, and had ≥1 database record dated ≥12 weeks after the initial bacillus Calmette-Guérin dose. Patients were followed until September 2018, the last date of available data, or in-hospital death. Patients receiving six doses of bacillus Calmette-Guérin at intervals of <21 days were considered to have completed induction according to guidelines. Time from initial bacillus Calmette-Guérin dose to subsequent bladder cancer treatment after the end of treatment was defined as the recurrence-free duration. RESULTS: Of 6140 patients identified (median age 73.0 years; 83.4% males), 4588 (74.7%) completed induction and 1552 (25.3%) did not. Median recurrence-free duration was 64.4, 77.7, and 31.6 months in the overall, complete-induction and incomplete-induction cohorts, respectively. Corresponding 3-year recurrence-free rate was 56.3%, 59.0%, and 48.2% in these groups. The rate of cystectomy was approximately 6% at 5 years in all cohorts. CONCLUSIONS: Approximately 75% of Japanese patients who undergo intravesical bacillus Calmette-Guérin treatment receive a guideline-compliant induction regimen, but outcomes were not satisfactory, highlighting the need for more effective treatments for non-muscle invasive bladder cancer.

Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study.

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380-4062 bp for gBRCA1, and between 3249-5681 bp and 6645-7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.

The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE).

INTRODUCTION: BRCA gene mutations are associated with hereditary ovarian cancer. BRCA plays a key role in genome integrity, and mutations result in an increased risk for ovarian cancer. Although various guidelines recommend BRCA testing in patients with ovarian cancer, data on germline BRCA (gBRCA) mutation frequency in ovarian cancer in Japan are scarce. OBJECTIVE: This study aimed to determine gBRCA1/2 mutations in Japanese patients with ovarian cancer, stratified by clinicopathological characteristics, and to assess patients' satisfaction with pre-test genetic counseling. METHODS: The CHARLOTTE study (CHARacterizing the cross-sectionaL approach to Ovarian cancer: geneTic TEsting of BRCA; UMIN000025597) is the first large multicenter epidemiological survey of Japanese women, aged ≥20, with newly diagnosed ovarian cancer (epithelial, primary peritoneal, or fallopian tube cancer), with histologically confirmed specimens. Patients were enrolled sequentially and underwent pre-test genetic counseling for BRCA testing. Blood samples were centrally tested for the presence or absence of known gBRCA mutations. A questionnaire was used to assess patient satisfaction with pre-test genetic counseling. RESULTS: A total of 634 patients with a mean age of 56.9 years were included. Most patients (84.2%) had epithelial ovarian cancer, and 51.1% had FIGO stage III-IV cancer. Nearly all patients (99.5%) received genetic counseling before the BRCA testing, either by an obstetrician-gynecologist (42.0%) or a clinical geneticist (42.0%). The overall prevalence of gBRCA1/2 mutations was 14.7% (93/634), with gBRCA1 mutations (9.9%) more common than gBRCA2 mutations (4.7%). High-grade serous carcinoma showed a prevalence of gBRCA mutations of 28.5%. Most patients were satisfied with pre-test counseling, irrespective of the service provider's professional position. DISCUSSION: Patients with high-grade serous carcinoma and family history of ovarian cancer had a slightly higher prevalence of gBRCA mutations, but none of the subgroups had considerably high gBRCA mutation prevalence. These data suggest that gBRCA testing should be carried out in all patients with ovarian cancer.

Induction of protumoral CD11c(high) macrophages by glioma cancer stem cells through GM-CSF.

Cancer stem cells (CSCs) are maintained under special microenvironment called niche, and elucidation and targeting of the CSC niche will be a feasible strategy for cancer eradication. Tumor-associated macrophages (TAMs) are known to be involved in cancer progression and thus can be a component of CSC niche. Although TAMs are known to play multiple roles in tumor progression, involvement of CSCs in TAM development fully remains to be elucidated. Using rat C6 glioma side population (SP) cells as a model of glioma CSCs, we here show that CSCs induce the TAM development by promoting survival and differentiation of bone marrow-derived monocytes. CSC-induced macrophages can be separated into two distinct subsets of cells, CD11c(low) and CD11c(high) cells. Interestingly, only the CD11c(high) subset of cells have protumoral activity, as shown by intracranial transplantation into immune-deficient mice together with CSCs. These CD11c(high) macrophages were observed in the tumor formed by co-transplantation with CSCs. Furthermore, CSCs produced GM-CSF and anti-GM-CSF antibody inhibited CSC-induced TAM development. In conclusion, CSCs have the ability to self-create their own niche involving TAMs through CSC-derived GM-CSF, which can thus be a therapeutic target in view of CSC niche disruption.

Tumor-associated macrophages as an emerging target against tumors: Creating a new path from bench to bedside.

Tumor-associated macrophages are a critical component of tumor microenvironments, which affect tumor growth, tumor angiogenesis, immune suppression, metastasis and chemoresistance. There is emerging evidence that many anticancer modalities currently used in the clinic have unique and distinct properties that modulate the recruitment, polarization and tumorigenic activities of macrophages in the tumor microenvironments. Educated tumor-associated macrophages significantly impact the clinical efficacies of and resistance to these anticancer modalities. Moreover, the development of drugs targeting tumor-associated macrophages, especially c-Fms kinase inhibitors and humanized antibodies targeting colony-stimulating factor-1 receptor, are in early clinical stages and show promising benefit for cancer patients. These experimental and clinical findings prompted us to further evaluate the potential targets that exhibit tumorigenic and immunosuppressive potential in a manner specific for tumor associated macrophages.

Immune regulation of therapy-resistant niches: emerging targets for improving anticancer drug responses.

Emerging evidence has unveiled a critical role for immunological parameters in predicting tumor prognosis and clinical responses to anticancer therapeutics. On the other hand, responsiveness to anticancer drugs greatly modifies the repertoires, phenotypes, and immunogenicity of tumor-infiltrating immune cells, serving as a critical factor to regulate tumorigenic activities and the emergence of therapy-resistant phenotypes. Tumor-associated immune functions are influenced by distinct or overlapping sets of therapeutic modalities, such as cytotoxic chemotherapy, radiotherapy, or molecular-targeted therapy, and various anticancer modalities have unique properties to influence the mode of cross-talk between tumor cells and immune cells in tumor microenvironments. Thus, it is critical to understand precise molecular machineries whereby each anticancer strategy has a distinct or overlapping role in regulating the dynamism of reciprocal communication between tumor and immune cells in tumor microenvironments. Such an understanding will open new therapeutic opportunities by harnessing the immune system to overcome resistance to conventional anticancer drugs.

[Immune regulation of cancer stem cells].

Emerging evidences have revealed the role of tumor-associated immune cells and their derivatives in the regulation of tumor progression. In particular, recent studies have clarified that various tumor-associated immune regulatory systems, which include tumor-infiltrating myeloid cells and pro-inflammatory cytokines, for regulating the maintenance and activation of cancer stem cells. The networks formed by immune cells and cancer stem cells play a critical role in further amplifying infiltration of pro-tumor immune cells and inflammatory cascades, and promoting cancer stemness. Further clarification about the immune-mediated regulation of cancer stem cell activities should provide therapeutic implication against cancer stem cells and treatment-resistant variants of cancer cells.

[Impact of molecular targeting therapy on tumor immunity].

Emerging evidence has been unveiled that major oncogenic pathways, which serve as a main focus for the molecular targeting therapies, play a pivotal role in establishing immunosuppressive tumor microenvironments. The modulation of various immune modulatory pathways, such as upregulation of PD-L1 by various oncogenic mutations such as EGFR, BRAF, activation of PI3K and JAK-Stat3 on tumor cells, may be critical in modulating tumor immune responses. Given the potential clinical impact of immune checkpoint blockade and other immunotherapeutic regimens as a future anticancer regimen, it is critical to clarify the mechanisms by which molecularly targetable oncogenes and tumor microenvironments influence quality of tumor immunosurveillance, which should provide a new strategy for suitable combinatorial approaches composing of molecular targeting and immunotherapies.

Yin and yang of tumor inflammation: how innate immune suppressors shape the tumor microenvironments.

Pattern recognition-mediated sensing systems direct host immunity towards either antitumor immunosurveillance or protumorigenic inflammation. These activities imply dual and conflicting roles in the regulation of tumor-associated inflammation. On the one hand, recent evidence has revealed that several signaling components and cell-surface receptors suppress innate immune signals and constitute a negative feedback machinery preventing excess and continuous inflammation within tumor microenvironments. On the other hand, these same components also negatively regulate intrinsic tumorigenic activities by targeting nuclear factor-kappaB (NF-κB)-mediated antiapoptotic and inflammatory signals. Furthermore, the activation status of innate immune suppressors may reflect the functional plasticity of interactions between tumor cells and innate immune cells and determine whether tumor inflammation supports anti- or pro-tumorigenic responses. Thus, innate immune suppressors may provide valuable information about the immunogenic or tumorigenic status of tumor-associated inflammation thereby serving as potential biomarkers that predict tumor progression. Comprehensive analysis for identifying general and unique features of each innate immune suppressor in the regulation of tumor inflammation should explore the development of new biomarkers for improving future therapeutic strategies.

Clinical significance of macrophage heterogeneity in human malignant tumors.

The fact that various immune cells, including macrophages, can be found in tumor tissue has long been known. With the recent introduction of the novel concept of macrophage differentiation into a classically activated phenotype (M1) and an alternatively activated phenotype (M2), the role of tumor-associated macrophages (TAMs) is gradually beginning to be elucidated. Specifically, in human malignant tumors, TAMs that have differentiated into M2 macrophages act as "protumoral macrophages" and contribute to the progression of disease. Based on recent basic and preclinical research, TAMs that have differentiated into protumoral or M2 macrophages are believed to be intimately involved in the angiogenesis, immunosuppression, and activation of tumor cells. In this paper, we specifically discuss both the role of TAMs in human malignant tumors and the cell-cell interactions between TAMs and tumor cells.

Colonization of an acid resistant Kingella denitrificans in the stomach may contribute to gastric dysbiosis by Helicobacter pylori.

In the stomach of a gastric ulcer patient who had been administered an anti-acid, a gram-negative and urease-negative bacillus similar in size to Helicobacter pylori was infected together with H. pylori. According to biochemical test and 16S rRNA gene analysis, the urease-negative bacterium was identified as Kingella denitrificans, a human nasopharyngeal commensal. In contrast to the standard strain of K. denitrificans, the isolate showed catalase activity, did not produce acid from glucose, and exhibited acid tolerance. Acid tolerance of H. pylori was increased by cocultivation with the K. denitrificans isolate, but not with other isolates of K. denitrificans. Disruption of physiological and immunological niche by dysbiotic colonization of bacterium may provide pathological attributes to human stomach. Collectively, a careful administration of anti-acids to the elderly, especially those with atrophic gastritis, is necessary to avoid repression of the gastric barrier to bacteria.

Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells.

Recent evidence has unveiled the critical role of tumor cells with stem cell activities in tumorigenicity and drug resistance, but how tumor microenvironments regulate cancer stem/initiating cells (CSCs) remains unknown. We clarified the role of tumor-associated macrophages (TAMs) and their downstream factor milk-fat globule-epidermal growth factor-VIII (MFG-E8) in the regulation of CSC activities. Bone marrow chimeric systems and adoptive cell transfers elucidated the importance of MFG-E8 from TAMs in conferring to CSCs with the ability to promote tumorigenicity and anticancer drug resistance. MFG-E8 mainly activates signal transducer and activator of transcription-3 (Stat3) and Sonic Hedgehog pathways in CSCs and further amplifies their anticancer drug resistance in cooperation with IL-6. Thus, the pharmacological targeting of key factors derived from tumor-associated inflammation provides a unique strategy to eradicate therapy-resistant tumors by manipulating CSC activities.

Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas.

Cancer vaccines have been developed to instruct the endogenous immune responses to autologous tumors and to generate durable clinical responses. However, the therapeutic benefits of cancer vaccines remain insufficient due to the multiple immunosuppressive signals delivered by tumors. Thus, to improve the clinical efficacy of cancer immunotherapy, it is important to develop new modalities to overcome immunosuppressive tumor microenvironments and elicit effective antitumor immune responses. In this study, we show that novel monoclonal antibodies (mAbs) specifically targeting either T cell immunoglobulin mucin protein-3 (TIM-3) or T cell immunoglobulin mucin protein-4 (TIM-4) enhance the therapeutic effects of vaccination against established B16 murine melanomas. This is true for vaccination with irradiated B16 melanoma cells engineered to express the flt3 ligand gene (FVAX). More importantly, combining anti-TIM-3 and anti-TIM-4 mAbs markedly increased vaccine-induced antitumor responses against established B16 melanoma. TIM-3 blockade mainly stimulated antitumor effector activities via natural killer cell-dependent mechanisms, while CD8(+) T cells served as the main effectors induced by anti-TIM-4 mAb. Our findings reveal that therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy for improving the clinical efficacy of cancer immunotherapy.

Enhancing the clinical activity of granulocyte-macrophage colony-stimulating factor-secreting tumor cell vaccines.

A comparative analysis of vaccination with irradiated, murine tumor cells engineered to express a large number of immunostimulatory molecules established the superior ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to evoke potent, specific, and long-lasting anti-tumor immunity. Early stage clinical testing of this vaccination strategy in patients with diverse solid and hematologic malignancies revealed the consistent induction of a coordinated humoral and cellular reaction that effectuated substantial tumor destruction. Nonetheless, most subjects eventually succumbed to progressive disease, implying that additional immune defects remained to be addressed. More detailed investigations of the mechanisms underlying protective immunity in murine systems together with the characterization of the anti-tumor reactions of patients who achieved durable clinical benefits in response to immunotherapy uncovered several pathways that restrain the efficacy of GM-CSF-secreting tumor cell vaccines. These include milk fat globule epidermal growth factor protein-8 expansion of forkhead box protein 3+ regulatory T cells, cytotoxic T-lymphocyte antigen-4-mediated negative costimulation, and soluble major histocompatibility complex class I chain-related protein A suppression of NKG2D-dependent innate and adaptive anti-tumor cytotoxicity. Together, these results define key regulatory circuits that attenuate immune-mediated tumor destruction and suggest novel combinatorial therapies that might enhance the clinical activity of GM-CSF-secreting tumor cell vaccines.

Deciphering the clinical features of heterogeneous stage III non-small cell lung cancer in Japanese real-world clinical practice: Expanded cohort of the SOLUTION study.

OBJECTIVES: To evaluate the actual treatment patterns with respective outcomes and the patient characteristics of stage III non-small cell lung cancer (NSCLC) in Japan. MATERIALS AND METHODS: Patients (aged ≥20 years at diagnosis) who were diagnosed with stage III NSCLC between January 2013 and December 2014 and underwent surgery, chemoradiotherapy (CRT), chemotherapy (CT), or radiotherapy (RT) at 11 institutions in Japan were consecutively registered in this retrospective, observational study (SOLUTION; UMIN000031385). Study measures included patient characteristics, first-line treatments, overall survival (OS), progression-free survival, objective response rate, and incidence of radiation-related adverse events. RESULTS: The study population comprised 744 patients. The tumors were classified as stage IIIA and IIIB in 58.9% and 41.1% of patients, respectively. The tumors were considered resectable at diagnosis in 25.0% of patients. First-line treatments were surgery (20.0%), CRT (46.1%), CT (22.2%), and RT (11.7%). The median OS (mOS) in the overall population was 25.4 months and the 3-year OS rate was 38.7%. Among the four first-line treatment cohorts, OS most favored the surgery cohort: mOS was 43.4 months and the 3-year OS rate was 53.8%. Prognostic factors for OS in each treatment modality were analyzed using multivariable analysis and included the following: age, performance status, and histological type for the surgery cohort; sex, histological type, and primary lesion location (lower lobe) for the CRT cohort; and performance status and clinical stage for the RT cohort. The timing of peak incidence of pneumonitis from the start of first-line treatment was 18-20 and 12-14 weeks in the CRT and RT cohorts, respectively. CONCLUSION: Patients with clinical stage III NSCLC received a variety of treatments selected to the clinical background and tumor status, and we clarified the outcome and prognostic factors. These findings will be a useful reference for future studies evaluating newly introduced treatments for stage III NSCLC.

Protein disulfide isomerases are antibody targets during immune-mediated tumor destruction.

The identification of cancer antigens that contribute to transformation and are linked with immune-mediated tumor destruction is an important goal for immunotherapy. Toward this end, we screened a murine renal cell carcinoma cDNA expression library with sera from mice vaccinated with irradiated tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor (GM-CSF). Multiple nonmutated, overexpressed proteins that function in tumor cell migration, protein/nucleic acid homeostasis, metabolism, and stress responses were detected. Among these, the most frequently recognized clone was protein disulfide isomerase (PDI). High titer antibodies to human PDI were similarly induced in an acute myeloid leukemia patient who achieved a complete response after vaccination with irradiated, autologous GM-CSF-secreting tumor cells in the setting of nonmyeloablative allogeneic bone marrow transplantation. Moreover, ERp5, a closely related disulfide isomerase involved in major histocompatibility complex (MHC) class I chain-related protein A (MICA) shedding, also evoked potent humoral reactions in diverse solid and hematologic malignancy patients who responded to GM-CSF-secreting tumor cell vaccines or antibody blockade of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Together, these findings reveal the unexpected immunogenicity of PDIs and raise the possibility that these gene products might serve as targets for therapeutic monoclonal antibodies.

MHC class I chain-related protein A antibodies and shedding are associated with the progression of multiple myeloma.

Monoclonal gammopathy of undetermined significance (MGUS) is a common disorder of aging and a precursor lesion to full-blown multiple myeloma (MM). The mechanisms underlying the progression from MGUS to MM are incompletely understood but include the suppression of innate and adaptive antitumor immunity. Here, we demonstrate that NKG2D, an activating receptor on natural killer (NK) cells, CD8(+) T lymphocytes, and MHC class I chain-related protein A (MICA), an NKG2D ligand induced in malignant plasma cells through DNA damage, contribute to the pathogenesis of MGUS and MM. MICA expression is increased on plasma cells from MGUS patients compared with normal donors, whereas MM patients display intermediate MICA levels and a high expression of ERp5, a protein disulfide isomerase linked to MICA shedding (sMICA). MM, but not MGUS, patients harbor circulating sMICA, which triggers the down-regulation of NKG2D and impaired lymphocyte cytotoxicity. In contrast, MGUS, but not MM, patients generate high-titer anti-MICA antibodies that antagonize the suppressive effects of sMICA and stimulate dendritic cell cross-presentation of malignant plasma cells. Bortezomib, a proteasome inhibitor with anti-MM clinical efficacy, activates the DNA damage response to augment MICA expression in some MM cells, thereby enhancing their opsonization by anti-MICA antibodies. Together, these findings reveal that the alterations in the NKG2D pathway are associated with the progression from MGUS to MM and raise the possibility that anti-MICA monoclonal antibodies might prove therapeutic for these disorders.