Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia

Banerjee, Priyanka; Ivan, Cristina; Galletti, G; Clise-Dwyer, Karen; Barbaglio, Federica; Scarfò, Lydia; Aracil, Miguel; Klein, Christian; Wierda, William G.; Plunkett, William; Caligaris-Cappio, Federico; Gandhi, Varsha; Keating, Michael J.; Bertilaccio, Maria Teresa Sabrina

doi:10.1158/2326-6066.cir-19-0152

Cited by 44 publications

(34 citation statements)

References 51 publications

(77 reference statements)

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“…One additional observation was the decrease in the cell surface levels of PD-L1, which might contribute to reinforce the immune surveillance action of the adaptive immune system against tumor cells [ 43 , 60 ].…”

Section: Discussionmentioning

confidence: 99%

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Povo‐Retana

Mojena

Stremtan

et al. 2020

Cancers

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Background: Tumor-associated macrophages (TAMs) play a crucial role in suppressing the immunosurveillance function of the immune system that prevents tumor growth. Indeed, macrophages can also be targeted by different chemotherapeutic agents improving the action over immune checkpoints to fight cancer. Here we describe the effect of trabectedin and lurbinectedin on human macrophage cell viability and function. Methods: Blood monocytes from healthy donors were differentiated into macrophages and exposed to different stimuli promoting functional polarization and differentiation into tumor-associated macrophages. Cells were challenged with the chemotherapeutic drugs and the effects on cell viability and function were analyzed. Results: Human macrophages exhibit at least two different profiles in response to these drugs. One-fourth of the blood donors assayed (164 individuals) were extremely sensitive to trabectedin and lurbinectedin, which promoted apoptotic cell death. Macrophages from other individuals retained viability but responded to the drugs increasing reactive oxygen production and showing a rapid intracellular calcium rise and a loss of mitochondrial oxygen consumption. Cell-membrane exposure of programmed-death ligand 1 (PD-L1) significantly decreased after treatment with therapeutic doses of these drugs, including changes in the gene expression profile of hypoxia-inducible factor 1 alpha (HIF-1α)-dependent genes, among other. Conclusions: The results provide evidence of additional onco-therapeutic actions for these drugs.

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Section: Discussionmentioning

confidence: 99%

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Povo‐Retana

Mojena

Stremtan

et al. 2020

Cancers

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“…A preclinical study recently showed in a chronic lymphocytic leukemia mouse model that trabectedin induced leukemic cell death and depletion of the immuno-suppressive myeloid-derived suppressor cells and TAMs [102]. Anti-tumor activity by trabectedin, through effects on TAMs, has also been reported in pre-clinical models of skeletal metastatic prostate tumor, melanoma, and pancreatic tumor [103][104][105].…”

Section: Strategies To Deplete Tamsmentioning

confidence: 97%

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Anfray

Ummarino

Andón

et al. 2019

Cells

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205

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: Established evidence demonstrates that tumor-infiltrating myeloid cells promote rather than stop-cancer progression. Tumor-associated macrophages (TAMs) are abundantly present at tumor sites, and here they support cancer proliferation and distant spreading, as well as contribute to an immune-suppressive milieu. Their pro-tumor activities hamper the response of cancer patients to conventional therapies, such as chemotherapy or radiotherapy, and also to immunotherapies based on checkpoint inhibition. Active research frontlines of the last years have investigated novel therapeutic strategies aimed at depleting TAMs and/or at reprogramming their tumor-promoting effects, with the goal of re-establishing a favorable immunological anti-tumor response within the tumor tissue. In recent years, numerous clinical trials have included pharmacological strategies to target TAMs alone or in combination with other therapies. This review summarizes the past and current knowledge available on experimental tumor models and human clinical studies targeting TAMs for cancer treatment.

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“…In CLL, trabectedin has shown to induce cytotoxic effects in leukemic cells and concomitantly exerts immunomodulatory activity on several cell types of the microenvironment. It depletes myeloid-derived suppressor cells and tumor-associated macrophages and induces T cell response [ 71 ].…”

Section: Introductionmentioning

confidence: 99%

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

Fiorcari

Maffei

Atene

et al. 2021

Cells

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Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries and is an example of hematological disease where cooperation between genetic defects and tumor microenvironmental interaction is involved in pathogenesis. CLL is a disease that is considered as “addicted to the host”; indeed, the crosstalk between leukemic cells and the tumor microenvironment is essential for leukemic clone maintenance supporting CLL cells’ survival, proliferation, and protection from drug-induced apoptosis. CLL cells are not innocent bystanders but actively model and manipulate the surrounding microenvironment to their own advantage. Besides the different players involved in this crosstalk, nurse-like cells (NLC) resemble features related to leukemia-associated macrophages with an important function in preserving CLL cell survival and supporting an immunosuppressive microenvironment. This review provides a comprehensive overview of the role played by NLC in creating a nurturing and permissive milieu for CLL cells, illustrating the therapeutic possibilities in order to specifically target and re-educate them.

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Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia

Cited by 44 publications

References 51 publications

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights

Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses

Nurse-Like Cells and Chronic Lymphocytic Leukemia B Cells: A Mutualistic Crosstalk inside Tissue Microenvironments

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