Preneoplastic lesions carry many of the antigenic targets found in cancer cells but often exhibit prolonged dormancy. Understanding how the host response to premalignancy is maintained and altered during malignant transformation is needed to prevent cancer. To understand the immune microenvironment in precursor monoclonal gammopathy of undetermined significance (MGUS) and myeloma, we analyzed bone marrow immune cells from 12 healthy donors and 26 patients with MGUS/myeloma by mass cytometry and concurrently profiled transcriptomes of 42,606 single immune cells from these bone marrow samples. Compared with age-matched healthy donors, memory T cells from both MGUS and myeloma patients exhibited greater terminal effector differentiation. However, memory T cells in MGUS show greater enrichment of stem-like TCF1/7 ^hi cells. Clusters of T cells with stem-like and tissue residence genes were also found to be enriched in MGUS by single-cell transcriptome analysis. Early changes in both NK and myeloid cells were also observed in MGUS. Enrichment of stem-like T cells correlated with a distinct genomic profile of myeloid cells and levels of Dickkopf-1 in bone marrow plasma. These data describe the landscape of changes in both innate and adaptive immunity in premalignancy and suggest that attrition of the bone marrow–resident T cell compartment because of loss of stem-like cells may underlie loss of immune surveillance in myeloma.

BACKGROUND: PD-1 and PD-L1 have been studied interchangeably in the clinic as checkpoints to reinvigorate T cells in diverse tumor types. Data for biologic effects of checkpoint blockade in human premalignancy are limited. METHODS: We analyzed the immunologic effects of PD-L1 blockade in a clinical trial of atezolizumab in patients with asymptomatic multiple myeloma (AMM), a precursor to clinical malignancy. Genomic signatures of PD-L1 blockade in purified monocytes and T cells in vivo were also compared with those following PD-1 blockade in lung cancer patients. Effects of PD-L1 blockade on monocyte-derived DCs were analyzed to better understand its effects on myeloid antigen-presenting cells. RESULTS: In contrast to anti–PD-1 therapy, anti–PD-L1 therapy led to a distinct inflammatory signature in CD14 ⁺ monocytes and increase in myeloid-derived cytokines (e.g., IL-18) in vivo. Treatment of AMM patients with atezolizumab led to rapid activation and expansion of circulating myeloid cells, which persisted in the BM. Blockade of PD-L1 on purified monocyte-derived DCs led to rapid inflammasome activation and synergized with CD40L-driven DC maturation, leading to greater antigen-specific T cell expansion. CONCLUSION: These data show that PD-L1 blockade leads to distinct systemic immunologic effects compared with PD-1 blockade in vivo in humans, particularly manifest as rapid myeloid activation. These findings also suggest an additional role for PD-L1 as a checkpoint for regulating inflammatory phenotype of myeloid cells and antigen presentation in DCs, which may be harnessed to improve PD-L1–based combination therapies. TRIAL REGISTRATION: NCT02784483. FUNDING: This work is supported, in part, by funds from NIH/NCI (NCI CA197603, CA238471, and CA208328).

A role for antigen-driven stimulation has been proposed in the pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) based largely on the binding properties of monoclonal Ig. However, insights into antigen binding to clonal B cell receptors and in vivo responsiveness of the malignant clone to antigen-mediated stimulation are needed to understand the role of antigenic stimulation in tumor growth. Lysolipid-reactive clonal Ig were detected in Gaucher disease (GD) and some sporadic gammopathies. Here, we show that recombinant Ig (rIg) cloned from sort-purified single tumor cells from lipid-reactive sporadic and GD-associated gammopathy specifically bound lysolipids. Liposome sedimentation and binding assays confirmed specific interaction of lipid-reactive monoclonal Ig with lysolipids. The clonal nature of lysolipid-binding Ig was validated by protein sequencing. Gene expression profiling and cytogenetic analyses from 2 patient cohorts showed enrichment of nonhyperdiploid tumors in lipid-reactive patients. In vivo antigen-mediated stimulation led to an increase in clonal Ig and plasma cells (PCs) in GD gammopathy and also reactivated previously suppressed antigenically related nonclonal PCs. These data support a model wherein antigenic stimulation mediates an initial polyclonal phase, followed by evolution of monoclonal tumors enriched in nonhyperdiploid genomes, responsive to underlying antigen. Targeting underlying antigens may therefore prevent clinical MM.

Multiple myeloma (MM) is a common hematologic malignancy, but due to its incurable nature, patients experience many relapses in their lifetime and hence face unique challenges. This mixed-methods study consisting of an online survey and subsequent focus groups aimed to understand how social and identity experiences affected the diagnostic, treatment, and care journey for patients with MM. Twenty-three adult patients with MM participated in this study. The survey participants identified common determinants negatively impacting their health, including mental health concerns (experienced by 90.5% of respondents), worries about food shortage (42.9%), and transportation concerns (28.6%). Focus group participants described high physical and mental health burdens associated with MM. Frequent monitoring, fear of a relapse, and unpredictable side effects contributed to high anxiety. Participants indicated that MM differed from other types of cancer and chronic health conditions in many ways, particularly how and where the diagnosis was made, disease progression and relapse, treatments and side effects, and financial concerns. Most participants (65.0%) reported ≥1 social need that negatively impacted health outcomes including lack of knowledge about MM, financial instability, and lack of insurance, transportation, and social support. The findings reveal that patients with MM continually experience patient-specific mental and physical health burdens indicating high unmet needs throughout the disease journey.