Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells

Varikuti, Sanjay; Singh, Bhawana; Volpedo, Greta; Ahirwar, Dinesh K.; Jha, Bijay Kumar; Saljoughian, Noushin; Viana, Agostinho Gonçalves; Verma, Chaitenya; Hamza, Omar; Halsey, Gregory; Holcomb, Erin A.; Maryala, Ritvik; Oghumu, Steve; Ganju, Ramesh K.; Satoskar, Abhay R.

doi:10.1038/s41416-020-0743-8

Cited by 58 publications

(43 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…DCs are part of normal differentiation from MDSCs. In pathological conditions, such as infections, trauma, sepsis, transpkantation, cancer or some autoimmune diseases, the differentiation of IMCs into mature myeloid cells, such as DCs or macrophages, were partially blocked, resulting in the expansion of MDSCs [ 39 ]. Therefore, antigen-specific T lymphocyte immunity may be restricted by this reason in the context of tumor microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression

Gao

et al. 2020

Cell Commun Signal

View full text Add to dashboard Cite

Backgound: Although Myeloid-derived suppressor cells (MDSCs) have a prominent ability to suppress the immune responses of T lymphocytes and propel tumor immune escape, a lack of profound systemic immunesuppression in tumor-bearing mice and tumor patients. The underlying mechanism of these remains unclear. Methods: For this purpose, renal cancer-derived exosomes (RDEs) were first labeled with PKH67 and been observed the internalization by MDSCs. Flow cytometry analysis showed the proportion and activity change of MDSCs in spleen and bone marrow induced by RDEs. Further, western blot experiments were used to verify triggered mechanism of MDSCs by RDEs. Finally, proliferation and cytotoxicity of cytotoxic T lymphocytes (CTLs) cocultured with MDSCs in vitro and a series of experiments in vivo were performed to demonstrate the specific inhibitory effect of RDEs-induced MDSCs. Results: This study suggested that RDEs crucially contributed to presenting antigenic information, activating and driving specific immunosuppressive effect to MDSCs. HSP70, which is highly expressed in RDEs, initiate this process in a toll like receptor 2 (TLR2)-dependent manner. Importantly, RDEs-induced MDSCs could exert an antigen-specific immunosuppression effect on CTL and specific promote renal tumors-growth and immune escape in consequence. Conclusion: The immunosuppression mediated by MDSCs which is induced by RDEs is antigen-specific. HSP70, which is highly expressed in RDEs, plays a pivotal role in this process. Targeted abrogating the function of MDSCs, or eliminating the expression of HSP70 in exosomes, or blocking the crosstalk between them provides a new direction and theoretical support for future immunotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression

Gao

et al. 2020

Cell Commun Signal

View full text Add to dashboard Cite

show abstract

“…Hence, the types and distribution of TAMs and MDSCs in breast cancer should be investigated in accordance with the breast cancer subtype, tumor stage, primary or metastatic tumor tissue, and metastatic sites for precise target therapy. Second, adjuvant treatment modality including chemotherapy and radiotherapy could affect TAMCs [206][207][208][209][210], or TAMCs itself could elicit resistance to adjuvant therapies [211]. Furthermore, TAMC-targeting agents influence responses to chemotherapy and radiotherapy [212][213][214]; these secondary effects should be considered when adjuvant therapies and TAMC-targeting agents are concurrently applied.…”

Section: Resultsmentioning

confidence: 99%

Role of Tumor-Associated Myeloid Cells in Breast Cancer

Jin

Koo

2020

Cells

View full text Add to dashboard Cite

Stromal immune cells constitute the tumor microenvironment. These immune cell subsets include myeloid cells, the so-called tumor-associated myeloid cells (TAMCs), which are of two types: tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Breast tumors, particularly those in human epidermal growth factor receptor 2 (HER-2)-positive breast cancer and triple-negative breast cancer, are solid tumors containing immune cell stroma. TAMCs drive breast cancer progression via immune mediated, nonimmune-mediated, and metabolic interactions, thus serving as a potential therapeutic target for breast cancer. TAMC-associated breast cancer treatment approaches potentially involve the inhibition of TAM recruitment, modulation of TAM polarization/differentiation, reduction of TAM products, elimination of MDSCs, and reduction of MDSC products. Furthermore, TAMCs can enhance or restore immune responses during cancer immunotherapy. This review describes the role of TAMs and MDSCs in breast cancer and elucidates the clinical implications of TAMs and MDSCs as potential targets for breast cancer treatment.

show abstract

“…Ibrutinib's performance varied greatly between animal and human studies in the trials described [39,40]. These contrasting results are multicausal.…”

Section: Discussionmentioning

confidence: 99%

“…Varikuti et al [40] used an orthotopic mouse breast cancer model to investigate ibrutinib's effect on tumor progression and metastasis. Mice were injected with tumor cells resembling a luminal b subtype [41].…”

Section: Breast Cancermentioning

confidence: 99%

Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review

Metzler

Burla

Fink

et al. 2020

IJMS

View full text Add to dashboard Cite

Ibrutinib is an orally available, small-molecule tyrosine kinase inhibitor. Its main purpose is to inhibit Bruton’s tyrosine kinase (BTK), an enzyme that is crucial in B cell development. It is FDA approved for the treatment of certain hematological malignancies. Several promising off-target drug effects have led to multiple, mostly preclinical investigations regarding its use in solid tumors. Unfortunately, data on its effectiveness in gynecological malignancies are limited, and (systematic) reviews are missing. The objective of this review was to summarize the existing literature and to analyze the evidence of ibrutinib as a treatment option in gynecological malignancies, including breast cancer. Studies were identified in MEDLINE and EMBASE using a defined search strategy, and preclinical or clinical research projects investigating ibrutinib in connection with these malignancies were considered eligible for inclusion. Our findings showed that preclinical studies generally confirm ibrutinib’s efficacy in cell lines and animal models of ovarian, breast, and endometrial cancer. Ibrutinib exerts multiple antineoplastic effects, such as on-target BTK inhibition, off-target kinase inhibition, and immunomodulation by interference with myeloid-derived suppressor cells (MDSCs), programmed death-ligand 1 (PD-L1), and T cell response. These mechanisms were elaborated and discussed in the context of the evidence available. Further research is needed in order to transfer the preclinical results to a broader clinical appliance.

show abstract

Ibrutinib treatment inhibits breast cancer progression and metastasis by inducing conversion of myeloid-derived suppressor cells to dendritic cells

Cited by 58 publications

References 52 publications

Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression

Renal cancer-derived exosomes induce tumor immune tolerance by MDSCs-mediated antigen-specific immunosuppression

Role of Tumor-Associated Myeloid Cells in Breast Cancer

Ibrutinib in Gynecological Malignancies and Breast Cancer: A Systematic Review

Contact Info

Product

Resources

About