Neoplastic plasma cells generate an inflammatory environment within bone marrow and markedly alter the distribution of T cells between lymphoid compartments

Goodyear, Oliver; Essex, Sarah; Anandram, Seetharam; Basu, Supratik; Moss, Paul; Pratt, Guy

doi:10.18632/oncotarget.16628

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…Our study revealed a tumor load dependent inflammatory circuit in MM with the release of CXCL9/10/11 from myeloid cells causing the migration of CXCR3+ inflammatory T cells from the periphery to the BM, in line with previous reports in the context of cancer and vaccinations [33][34][35]. Inflammatory T cells and NK cells in turn act as major drivers for IFNg-mediated BM changes in a self-propelling circuit.…”

Section: Discussionsupporting

confidence: 90%

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

Lutz,

Grünschläger,

Simon

et al. 2023

Preprint

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The long-term consequences of cancer or cancer therapy on the patients’ immune system years after cancer-free survival remain poorly understood. Here, we have performed an in-depth characterization of the bone marrow ecosystem of multiple myeloma long-term survivors at initial diagnosis and up to 17 years following cancer-free survival. Using comparative single-cell analyses in combination with molecular, genomic and functional approaches, we demonstrate that multiple myeloma long-term survivors display pronounced alterations in their bone marrow microenvironment associated with impaired immunity. These immunological alterations were frequently driven by an inflammatory immune circuit fueled by the long-term persistence or resurgence of residual myeloma cells. Notably, even in the complete absence of any detectable residual disease for decades, sustained changes in the immune system were observed, suggesting an irreversible ‘immunological scarring’ caused by the initial exposure to the cancer and therapy. Collectively, our study provides key insights into the molecular and cellular bone marrow ecosystem of multiple myeloma long-term survivors, revealing reversible and irreversible alterations of the immune compartment, which can serve as diagnostic and predictive tools.Statement of significanceLarge-scale single-cell profiling of a unique cohort of multiple myeloma long-term survivors uncovered that exposure to cancer and its treatment causes both reversible and irreversible immune alterations associated with impaired immunity. These findings have far-reaching implications for the understanding of long-term immune alterations in cancer, which need to be considered also in the context of immune therapeutic approaches. Furthermore, our study demonstrates how cancer-associated immune trafficking can be used to predict disease re-initiation in the bone marrow, opening new avenues for minimally invasive disease monitoring.

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Section: Discussionsupporting

confidence: 90%

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

Lutz,

Grünschläger,

Simon

et al. 2023

Preprint

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“…Our data demonstrate for the first time that it is possible to increase activated BM NK cell infiltration with beneficial anti-myeloma effects by genetic deletion of Cxcr3 gene or by in vivo administration of anti-CXCR3 specific mAb. These results correlate with the negative role of CXCR3 activation on BM NK cell localization and with up-regulated levels of CXCR3 ligands in the MM-microenvironment [8, 39, 40].…”

Section: Discussionsupporting

confidence: 55%

Targeting of CXCR3 improves anti-myeloma efficacy of adoptively transferred activated natural killer cells

Bonanni

Antonangeli

Santoni

et al. 2019

j. immunotherapy cancer

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BackgroundThe peculiar multiple myeloma microenvironment, characterized by up-regulated levels of several inflammatory chemokines, including the CXCR3 receptor ligands CXCL9 and CXCL10, limits NK cell positioning into the bone marrow by interfering with CXCR4 function. It is still unclear if the consequent reduced influx of transferred cells into the tumor represents a potential limiting factor for the success of NK cell-based adoptive therapy. We hypothesize that inhibition of CXCR3 function on NK cells will result in increased tumor clearance, due to higher NK cell bone marrow infiltration.MethodsSince different activation protocols differently affect expression and function of homing receptors, we analyzed the bone marrow homing properties and anti-tumor efficacy of NK cells stimulated in vitro with two independent protocols. NK cells were purified from wild-type or Cxcr3−/− mice and incubated with IL-15 alone or with a combination of IL-12, IL-15, IL-18 (IL-12/15/18). Alternatively, CXCR3 function was neutralized in vivo using a specific blocking antibody. NK cell functional behavior and tumor growth were analyzed in bone marrow samples by FACS analysis.ResultsBoth activation protocols promoted degranulation and IFN-γ production by donor NK cells infiltrating the bone marrow of tumor-bearing mice, although IL-15 promoted a faster but more transient acquisition of functional capacities. In addition, IL-15-activated cells accumulated more in the bone marrow in a short time but showed lower persistence in vivo. Targeting of CXCR3 increased the bone marrow homing capacity of IL-15 but not IL12/15/18 activated NK cells. This effect correlated with a superior and durable myeloma clearance capacity of transferred cells in vivo.ConclusionsOur results demonstrate that in vitro activation affects NK cell anti-myeloma activity in vivo by regulating their BM infiltration. Furthermore, we provided direct evidence that CXCR3 restrains NK cell anti-tumor capacity in vivo according to the activation protocol used, and that the effects of NK cell-based adoptive immunotherapy for multiple myeloma can be improved by increasing their bone marrow homing through CXCR3 inhibition.

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“…Similarly, CXCR2-transduced NK cells have an increased ability to migrate toward renal cell carcinoma tumors in a ligand-specific manner, resulting in increased killing of target cells ( 342 ). As long as CXCL16 is found in the BM at high levels ( 343 ) and CXCL8, the CXCR1, and CXCR2 ligand is significantly elevated in MM ( 344 , 345 ), CLL ( 346 ), AML, and MDS patients ( 347 ), the targeting of CXCL16-CXCR6 and IL8-CXCR2/CXCR1 pathways should be studied in depth for hematologic malignancies.…”

Section: Restoring Migration and Homing Into Tumor Bed: A Matter Of C...mentioning

confidence: 99%

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

et al. 2022

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Despite the impressive results of autologous CAR-T cell therapy in refractory B lymphoproliferative diseases, CAR-NK immunotherapy emerges as a safer, faster, and cost-effective approach with no signs of severe toxicities as described for CAR-T cells. Permanently scrutinized for its efficacy, recent promising data in CAR-NK clinical trials point out the achievement of deep, high-quality responses, thus confirming its potential clinical use. Although CAR-NK cell therapy is not significantly affected by the loss or downregulation of its CAR tumor target, as in the case of CAR-T cell, a plethora of common additional tumor intrinsic or extrinsic mechanisms that could also disable NK cell function have been described. Therefore, considering lessons learned from CAR-T cell therapy, the emergence of CAR-NK cell therapy resistance can also be envisioned. In this review we highlight the processes that could be involved in its development, focusing on cytokine addiction and potential fratricide during manufacturing, poor tumor trafficking, exhaustion within the tumor microenvironment (TME), and NK cell short in vivo persistence on account of the limited expansion, replicative senescence, and rejection by patient’s immune system after lymphodepletion recovery. Finally, we outline new actively explored alternatives to overcome these resistance mechanisms, with a special emphasis on CRISPR/Cas9 mediated genetic engineering approaches, a promising platform to optimize CAR-NK cell function to eradicate refractory cancers.

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Neoplastic plasma cells generate an inflammatory environment within bone marrow and markedly alter the distribution of T cells between lymphoid compartments

Cited by 8 publications

References 48 publications

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

Multiple myeloma long-term survivors display sustained immune alterations decades after first line therapy

Targeting of CXCR3 improves anti-myeloma efficacy of adoptively transferred activated natural killer cells

Overcoming tumor resistance mechanisms in CAR-NK cell therapy

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