Inhibition of tumor‐associated macrophages by trabectedin improves the antitumor adaptive immunity in response to anti‐PD‐1 therapy

A considerable proportion of cancer patients are resistant or only partially responsive to immune checkpoint blockade immunotherapy. Tumor‐Associated Macrophages (TAMs) infiltrating the tumor stroma suppress the adaptive immune responses and, hence, promote tumor immune evasion. Depletion of TAMs or modulation of their protumoral functions is actively pursued, with the purpose of relieving this state of immunesuppression. We previously reported that trabectedin, a registered antitumor compound, selectively reduces monocytes and TAMs in treated tumors. However, its putative effects on the adaptive immunity are still unclear. In this study, we investigated whether treatment of tumor‐bearing mice with trabectedin modulates the presence and functional activity of T‐lymphocytes.

[1]  F. Grosso,et al.  Trabectedin for Patients with Advanced Soft Tissue Sarcoma: A Non-Interventional, Retrospective, Multicenter Study of the Italian Sarcoma Group , 2021, Cancers.

[2]  D. Aldinucci,et al.  Trabectedin overcomes doxorubicin-resistance, counteracts tumor-immunosuppressive reprogramming of monocytes and decreases xenograft growth in Hodgkin lymphoma. , 2020, Cancer letters.

[3]  L. Boscá,et al.  Specific Effects of Trabectedin and Lurbinectedin on Human Macrophage Function and Fate—Novel Insights , 2020, Cancers.

[4]  Clément Anfray,et al.  Targeting Tumor-Associated Macrophages in Anti-Cancer Therapies: Convincing the Traitors to Do the Right Thing , 2020, Journal of clinical medicine.

[5]  J. V. Van Ginderachter,et al.  Innate Immune Defense Mechanisms by Myeloid Cells That Hamper Cancer Immunotherapy , 2020, Frontiers in Immunology.

[6]  J. Pollard,et al.  Macrophage targeting in cancer , 2020, Annals of the New York Academy of Sciences.

[7]  Michele De Palma,et al.  Biology and therapeutic targeting of tumour‐associated macrophages , 2020, The Journal of pathology.

[8]  P. Sharma,et al.  Dissecting the mechanisms of immune checkpoint therapy , 2020, Nature Reviews Immunology.

[9]  P. Allavena,et al.  Current Strategies to Target Tumor-Associated-Macrophages to Improve Anti-Tumor Immune Responses , 2019, Cells.

[10]  J. Paul Robinson,et al.  Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition) , 2019, European journal of immunology.

[11]  C. Klein,et al.  Trabectedin Reveals a Strategy of Immunomodulation in Chronic Lymphocytic Leukemia , 2019, Cancer Immunology Research.

[12]  M. D’Incalci,et al.  Antimetastatic and antiangiogenic activity of trabectedin in cutaneous melanoma , 2019, Carcinogenesis.

[13]  P. Andreeva-Gateva,et al.  The place of trabectedin in the treatment of soft tissue sarcoma: an umbrella review of the level one evidence , 2019, Expert Opinion on Orphan Drugs.

[14]  Brian Ruffell,et al.  Macrophages as regulators of tumour immunity and immunotherapy , 2019, Nature Reviews Immunology.

[15]  O. Mir,et al.  A comprehensive review of the current evidence for trabectedin in advanced myxoid liposarcoma. , 2019, Cancer treatment reviews.

[16]  Y. Shiozawa,et al.  Trabectedin Reduces Skeletal Prostate Cancer Tumor Size in Association with Effects on M2 Macrophages and Efferocytosis12 , 2018, Neoplasia.

[17]  W. Goins,et al.  Myelolytic Treatments Enhance Oncolytic Herpes Virotherapy in Models of Ewing Sarcoma by Modulating the Immune Microenvironment , 2018, Molecular therapy oncolytics.

[18]  M. Zucchetti,et al.  Trabectedin and olaparib in patients with advanced and non-resectable bone and soft-tissue sarcomas (TOMAS): an open-label, phase 1b study from the Italian Sarcoma Group. , 2018, The Lancet. Oncology.

[19]  J. Pollard,et al.  Diverse Functions of Macrophages in Different Tumor Microenvironments. , 2018, Cancer research.

[20]  P. Allavena,et al.  Depletion of tumor-associated macrophages switches the epigenetic profile of pancreatic cancer infiltrating T cells and restores their anti-tumor phenotype , 2018, Oncoimmunology.

[21]  M. Colombo,et al.  Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors , 2017, Clinical Cancer Research.

[22]  J. Wargo,et al.  Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy , 2017, Cell.

[23]  Alberto Mantovani,et al.  Tumour-associated macrophages as treatment targets in oncology , 2017, Nature Reviews Clinical Oncology.

[24]  M. Cazzola,et al.  Antitumour activity of trabectedin in myelodysplastic/myeloproliferative neoplasms , 2017, British Journal of Cancer.

[25]  C. Ries,et al.  Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. , 2017, Journal for immunotherapy of cancer.

[26]  N. Colombo,et al.  Experience with trabectedin + pegylated liposomal doxorubicin for recurrent platinum-sensitive ovarian cancer unsuited to platinum rechallenge , 2016, Expert review of anticancer therapy.

[27]  Peter J. Murray,et al.  Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards , 2016, Nature Communications.

[28]  P. Allavena,et al.  Functional TRAIL receptors in monocytes and tumor-associated macrophages: A possible targeting pathway in the tumor microenvironment , 2016, Oncotarget.

[29]  P. Allavena,et al.  Tumor-associated macrophages and anti-tumor therapies: complex links , 2016, Cellular and Molecular Life Sciences.

[30]  C. Galmarini,et al.  Unique features of trabectedin mechanism of action , 2016, Cancer Chemotherapy and Pharmacology.

[31]  Shulan Zhang,et al.  Combined Trabectedin and anti-PD1 antibody produces a synergistic antitumor effect in a murine model of ovarian cancer , 2015, Journal of Translational Medicine.

[32]  C M Galmarini,et al.  Mode of action of trabectedin in myxoid liposarcomas , 2014, Oncogene.

[33]  P. Allavena,et al.  Trabectedin, a drug acting on both cancer cells and the tumour microenvironment , 2014, British Journal of Cancer.

[34]  Christina S. Leslie,et al.  CSF-1R inhibition alters macrophage polarization and blocks glioma progression , 2013, Nature Medicine.

[35]  M. Zucchetti,et al.  Role of macrophage targeting in the antitumor activity of trabectedin. , 2013, Cancer cell.

[36]  C. Galmarini,et al.  A Review of Trabectedin (ET-743): A Unique Mechanism of Action , 2010, Molecular Cancer Therapeutics.

[37]  P. Allavena,et al.  Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. , 2010, Cancer research.

[38]  Robin L. Jones,et al.  Efficacy of trabectedin (ecteinascidin-743) in advanced pretreated myxoid liposarcomas: a retrospective study. , 2007, The Lancet. Oncology.

[39]  P. Allavena,et al.  Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production. , 2005, Cancer research.