IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma.

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

Impact of Preoperative Intervertebral Disc Degeneration on Patient-Reported Outcome Measures After Lumbar Fusion.

OBJECTIVE: The Pfirrmann scoring system classifies lumbosacral disc degeneration based on magnetic resonance imaging signal intensity. The relationship between pre-existing disc degeneration and patient-reported outcome measures (PROMs) after one-level lumbar fusion is not well documented. The purpose of this study was to investigate the relationship between the severity of preoperative intervertebral disc degeneration and preoperative and postoperative PROMs in patients undergoing one-level lumbar fusion. METHODS: All adult patients who underwent posterior lumbar decompression and fusion or transforaminal lumbar interbody fusion between 2014 and 2022 were included. Patient demographics and comorbidities were extracted from medical records. Lumbar intervertebral discs on sagittal magnetic resonance imaging T2-weighted images were assessed by 2 independent graders utilizing Pfirrmann criteria. Grades I-III were categorized as low-grade disc degeneration, while IV-V were considered high grade. Multivariable linear regression assessed the impact of disc degeneration on PROMs. RESULTS: A total of 150 patients were included, of which 69 (46%) had low-grade disc degeneration, while 81 (54%) had high-grade degeneration. Patients with high-grade degeneration had increased preoperative visual analog scale (VAS)-Leg scores (6.10 vs. 4.54, P = 0.005) and displayed greater 1-year postoperative improvements in VAS-Back scores (-2.11 vs. -0.66, P = 0.002). Multivariable regression demonstrated Pfirrmann scores as independent predictors for both preoperative VAS-Leg scores (P = 0.004) and postoperative VAS-Back improvement (P = 0.005). CONCLUSIONS: In patients undergoing one-level lumbar fusion, higher Pfirmann scores were associated with increased preoperative leg pain and greater 1-year postoperative improvement in back pain. Further studies into the relationship of preoperative disc degeneration and their impact on postoperative outcomes may help guide clinical decision-making and patient expectations.

Tumor-associated macrophages in multiple myeloma: advances in biology and therapy.

Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow (BM) and represents the second most common hematological malignancy in the world. The MM tumor microenvironment (TME) within the BM niche consists of a wide range of elements which play important roles in supporting MM disease progression, survival, proliferation, angiogenesis, as well as drug resistance. Together, the TME fosters an immunosuppressive environment in which immune recognition and response are repressed. Macrophages are a central player in the immune system with diverse functions, and it has been long established that macrophages play a critical role in both inducing direct and indirect immune responses in cancer. Tumor-associated macrophages (TAMs) are a major population of cells in the tumor site. Rather than contributing to the immune response against tumor cells, TAMs in many cancers are found to exhibit protumor properties including supporting chemoresistance, tumor proliferation and survival, angiogenesis, immunosuppression, and metastasis. Targeting TAM represents a novel strategy for cancer immunotherapy, which has potential to indirectly stimulate cytotoxic T cell activation and recruitment, and synergize with checkpoint inhibitors and chemotherapies. In this review, we will provide an updated and comprehensive overview into the current knowledge on the roles of TAMs in MM, as well as the therapeutic targets that are being explored as macrophage-targeted immunotherapy, which may hold key to future therapeutics against MM.

Nanoparticle T cell engagers for the treatment of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common type of leukemia and has a 5-year survival rate of 25%. The standard-of-care for AML has not changed in the past few decades. Promising immunotherapy options are being developed for the treatment of AML; yet, these regimens require highly laborious and sophisticated techniques. We create nanoTCEs using liposomes conjugated to monoclonal antibodies to enable specific binding. We also recreate the bone marrow niche using our 3D culture system and use immunocompromised mice to enable use of human AML and T cells with nanoTCEs. We show that CD33 is ubiquitously present on AML cells. The CD33 nanoTCEs bind preferentially to AML cells compared to Isotype. We show that nanoTCEs effectively activate T cells and induce AML killing in vitro and in vivo. Our findings suggest that our nanoTCE technology is a novel and promising immuno-therapy for the treatment of AML and provides a basis for supplemental investigations for the validation of using nanoTCEs in larger animals and patients.

Bispecific T Cell Engagers for the Treatment of Multiple Myeloma: Achievements and Challenges.

MM is the second most common hematological malignancy and represents approximately 20% of deaths from hematopoietic cancers. The advent of novel agents has changed the therapeutic landscape of MM treatment; however, MM remains incurable. T cell-based immunotherapy such as BTCEs is a promising modality for the treatment of MM. This review article discusses the advancements and future directions of BTCE treatments for MM.