Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma

Racanelli, Vito; Leone, Patrizia; Frassanito, Maria Antonia; Brunetti, Claudia; Perosa, Federico; Ferrone, Soldano; Dammacco, Franco

doi:10.1182/blood-2009-06-228676

Cited by 69 publications

(77 citation statements)

References 30 publications

(39 reference statements)

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“…12,13,31 Moreover, it strengthens the idea that T-cell priming by DCs is not abolished or impaired, indicating that there is no tolerance to plasma cell tumors. These considerations call into question the other novel aspect of our study that pertains to the consequences of the interaction between DCs and live tumor plasma cells.…”

Section: Discussionsupporting

confidence: 53%

“…13 Now we provide evidence for a mechanism responsible for this downregulation that surprisingly involves the binding of CD28 expressed on tumor plasma cells with its ligands CD80/CD86 expressed on BM mDCs. For personal use only.…”

Section: Discussionmentioning

confidence: 99%

“…Fluorescein isothiocyanate (FITC)-conjugated Lineage mAb mix, phycoerythrin (PE)-cyanine 5 (Cy5)-conjugated anti-CD123 mAb, and PE-Cy5-conjugated anti-CD11c mAb were purchased from BD Biosciences; PE-Texas red (ECD)-conjugated anti-HLA-DR mAb, PE-conjugated anti-CD80 mAb, PE-conjugated anti-CD86 mAb, PE-conjugated anti-CD138 mAb, allophycocyanin (APC)-conjugated anti-CD28, and FITC-conjugated anti-CD8 mAb were purchased from Beckman Coulter; APC-conjugated anti-BDCA-1 (CD1c), APC-conjugated anti-BDCA-3 (CD141) and APC-conjugated anti-BDCA-2 (CD303), PEconjugated anti-IL-12 mAb, and PE-conjugated anti-IFN-a mAb were purchased from Miltenyi Biotec. The d mAb SY-5, MB1 mAb SJJ-3, z mAb NB1, LMP2 mAb SY-1, LMP7 mAb HB2, and LMP10 mAb TO-7, calreticulin mAb TO-11 were produced and characterized as described previously 13 and labeled with FITC by the use of the Lightning-Link FITC Conjugation Kit (Innova Biosciences). The PE-conjugated NY-ESO-1 157-165 -specific HLA-A*0201 pentamer was purchased from Proimmune.…”

Section: Immunofluorescence Staining and Fluorescent Labeling Of Cellsmentioning

confidence: 99%

“…Levels of protein expression here were quantified in units of molecular equivalents of soluble fluorochrome (MESF). 13 For cells stained with pentamers, the level of nonspecific binding was calculated from the background signal observed in cells from 4 HLA-A*0201-negative patients. In particular, the cutoff for pentamer-positive signals was set as the average background signal plus 3 SD.…”

Section: Fluorescence Microscopy and Flow Cytometrymentioning

confidence: 99%

“…Different studies have shown that DCs may promote myeloma-specific T-cell responses, 12,13 although they may also support plasma cell proliferation and survival via engagement of their CD80/86 receptors by the ligand CD28 on plasma cells. [14][15][16][17] Moreover, little information is available on DCs in the bone marrow (BM), which is the privileged site of clonal plasma cell proliferation, and therefore the main site of tumor-antigen expression.…”

mentioning

confidence: 99%

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Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Leone

Berardi

Frassanito

et al. 2015

Blood

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Key Points• Dendritic cells accumulate in the bone marrow of multiple myeloma patients.• Bone marrow dendritic cells play a dual, but opposing, role in multiple myeloma.Many researchers have speculated that the clinical progression from monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. However, evidence supporting this assumption is controversial, and no mechanism for the putative DC dysfunction has been demonstrated thus far. We studied DC subsets from the bone marrow of MM patients compared with those of MGUS patients and control subjects. We found that myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDCs and pDCs mature and are able to activate tumor-specific CD8 1 T cells. However, by interacting directly with CD28 on live (nonapoptotic) tumor plasma cells, bone marrow mDCs downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from human leukocyte antigen (HLA) class I-restricted CD8 1 T-cell killing. These results suggest that DCs play a dual, but opposing, role in MM: for one, DCs activate CD8 1 T cells against tumor plasma cells and, for the other, DCs protect tumor plasma cells from CD8 1 T-cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Section: Immunofluorescence Staining and Fluorescent Labeling Of Cellsmentioning

confidence: 99%

Section: Fluorescence Microscopy and Flow Cytometrymentioning

confidence: 99%

mentioning

confidence: 99%

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Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Leone

Berardi

Frassanito

et al. 2015

Blood

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Bispecific T‐cell engagers for treatment of multiple myeloma

Ravi

Costa

2022

American J Hematol

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Bispecific T cell engagers (TCE) derive from monoclonal antibodies and concomitantly engage a target on the surface of cancer cell and CD3 on the surface of T-cells. TCEs promote T cell activation and lysis of tumor cells. Most TCEs in development for multiple myeloma (MM) target the B cell maturation antigen (BCMA) and differ among themselves in structure, pharmacokinetics, route and schedule of administration. CD3/BCMA TCEs produce response in $60% of patients treated in phase 1 trials. TCEs are also in development targeting the G protein-coupled receptor, class C group 5 member D (GPRC5D) and the Fc receptor homologue 5 (FcRH5). Main toxicities are cytokine release syndrome and cytopenias. Here we review the current development and future directions of TCEs in MM.

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Chemotherapy‐induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death

Hodge

Garnett

Farsaci

et al. 2013

Intl Journal of Cancer

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248

199

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Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy-induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from immunogenic cell death. Docetaxel treatment of tumor cells did not induce ATP or HMGB1 secretion, or cell death. However, calreticulin exposure was observed in all cell lines examined after chemotherapy treatment. Killing by CEA, MUC-1, or PSA-specific CD8+ CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen-processing machinery, and mediated largely by calreticulin membrane translocation, as determined by functional knockdown of calreticulin, PERK, or calreticulin-blocking peptide. A docetaxel-resistant cell line was selected (MDR-1+, CD133+) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to immunogenic cell death and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy.

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Alterations in the antigen processing-presenting machinery of transformed plasma cells are associated with reduced recognition by CD8+ T cells and characterize the progression of MGUS to multiple myeloma

Cited by 69 publications

References 30 publications

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8+ T-cell killing

Bispecific T‐cell engagers for treatment of multiple myeloma

Chemotherapy‐induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death

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