Roles of mesenchymal stromal cells in the head and neck cancer microenvironment

Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of CetuximabProg-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

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A Pilot Study to Assess the Salivary Gland Regenerative Potential of Bone Marrow Mesenchymal Stromal Cells from Treated Head and Neck Cancer Patients

10.21203/rs.3.rs-965122/v1 ◽

2021 ◽

Author(s):

Grace C Blitzer ◽

Cristina Paz ◽

Annemarie Glassey ◽

Olga Ganz ◽

Jayeeta Giri ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Head And Neck Cancer ◽

Salivary Gland ◽

Clinical Study ◽

Head And Neck ◽

Neck Cancer ◽

Stromal Cells ◽

Preliminary Data ◽

Pilot Clinical Study

Abstract Background: Salivary dysfunction is a significant side effect of radiation therapy for head and neck cancer (HNC). Preliminary data suggests that mesenchymal stromal cells (MSCs) can improve salivary function. Whether MSCs from HNC patients who have completed chemoradiation are functionally similar to those from healthy patients is unknown. We performed a pilot clinical study to determine whether bone marrow-derived MSCs (BM-MSCs) from HNC patients could be used for the treatment of RT-induced salivary dysfunction.Methods: An IRB-approved pilot clinical study was untaken on HNC patients with xerostomia who had completed treatment two or more years prior. Patients underwent iliac crest bone marrow aspirate and BM-MSCs were isolated and cultured. Culture expanded BM-MSCs were stimulated with IFNγ and cryopreserved prior to reanimation and profiling for functional markers by flow cytometry and ELISA. BM-MSCs were additionally injected into mice with radiation-induced xerostomia and the changes in salivary gland histology were examined. Results: A total of six subjects were enrolled. BM-MSCs from all subjects were culture expanded to >20 million cells in a median of 15.5 days (range 8-20 days). Flow cytometry confirmed that cultured cells from HNC patients were BM-MSCs. Functional flow cytometry demonstrated that these IFNγ-stimulated BM-MSCs acquired an immunosuppressive phenotype. IFNγ-stimulated BM-MSCs from HNC patients were found to express GDNF, WNT1, and R-spondin 1 as well as pro-angiogenesis and immunomodulatory cytokines. In mice, IFNγ-stimulated BM-MSCs decreased the loss of acinar cells decreased the formation of fibrosis. Conclusions: BM-MSCs from previously treated HNC patients can be expanded for auto-transplantation and are functionally active. Furthermore, IFNγ-stimulated BM-MSCs express proteins implicated in salivary gland regeneration. This study provides preliminary data supporting the feasibility of using autologous BM-MSCs from HNC patients to treat RT-induced salivary dysfunction.Trial Registration: NCT04007081, Registered July 5, 2019, https://clinicaltrials.gov/ct2/show/NCT04007081

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IL-6 in the Ecosystem of Head and Neck Cancer: Possible Therapeutic Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms222011027 ◽

2021 ◽

Vol 22 (20) ◽

pp. 11027

Author(s):

Michal Španko ◽

Karolína Strnadová ◽

Aleš Jan Pavlíček ◽

Pavol Szabo ◽

Ondřej Kodet ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Interleukin 6 ◽

Tumor Therapy ◽

Cancer Microenvironment ◽

Biological Processes ◽

Therapeutic Approaches ◽

Distinct Role

Interleukin-6 (IL-6) is a highly potent cytokine involved in multiple biological processes. It was previously reported to play a distinct role in inflammation, autoimmune and psychiatric disorders, ageing and various types of cancer. Furthermore, it is understood that IL-6 and its signaling pathways are substantial players in orchestrating the cancer microenvironment. Thus, they appear to be potential targets in anti-tumor therapy. The aim of this article is to elucidate the role of IL-6 in the tumor ecosystem and to review the possible therapeutic approaches in head and neck cancer.

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Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Stem Cell Reviews and Reports ◽

10.1007/s12015-021-10159-1 ◽

2021 ◽

Author(s):

Greet Merckx ◽

Melissa Lo Monaco ◽

Ivo Lambrichts ◽

Uwe Himmelreich ◽

Annelies Bronckaers ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Stromal Cells ◽

Dental Pulp ◽

Human Dental Pulp

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Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

10.21203/rs.3.rs-76749/v1 ◽

2020 ◽

Author(s):

Greet Merckx ◽

Melissa Lo Monaco ◽

Ivo Lambrichts ◽

Uwe Himmelreich ◽

Annelies Bronckaers ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Stromal Cells ◽

Dental Pulp ◽

Mesenchymal Transition ◽

Anti Cancer ◽

Tumour Homing

Abstract Background: Head and neck cancer (HNC) is one of the most common cancers, associated with a huge mortality and morbidity. In order to improve patient outcomes, more efficient and targeted therapies are essential. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) express tumour homing capacity, which could be exploited to target anti-cancer drug delivery to the tumour region and reduce adverse side-effects. Nevertheless, dental pulp stromal cells (DPSCs), an MSC-like population present in teeth, could offer important clinical benefits because of their easy isolation and superior proliferation compared to BM-MSCs. Therefore, we aimed to elucidate the tumour homing and safe usage of DPSCs to treat HNC. Methods: The in vivo survival as well as the effect of intratumourally administered DPSCs on tumour aggressiveness was tested in a HNC xenograft mouse model by using bioluminescence imaging (BLI), (immuno)histology and qRT-PCR. Furthermore, the in vitro and in vivo tumour homing capacity of DPSCs towards a HNC cell line were evaluated by a transwell migration assay and BLI, respectively. Results: Intratumourally injected DPSCs survived for at least two weeks in the tumour micro-environment and had no significant influence on tumour morphology, growth, angiogenesis and epithelial-to-mesenchymal transition. In addition, DPSCs migrated towards tumour cells in vitro, which could not be confirmed after their in vivo intravenous, intraperitoneal or peritumoural injection under the tested experimental conditions. Conclusions: Our research suggests that intratumourally delivered DPSCs might be used as safe factories for the continuous delivery of anti-cancer drugs in HNC. Nevertheless, further optimization as well as efficacy studies are necessary to understand and improve in vivo tumour homing and determine the optimal experimental set-up of stem cell-based cancer therapies, including dosing and timing.

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