Biology subjects

Hasani-Sadrabadi, M. M.

Publications and source records attributed to Hasani-Sadrabadi, M. M..

4 recordsLinked to original sources

bioRxiv2021

Global anti-tumor immunity after localized, bioengineered Treg depletion

Over 90% of deaths from cancer occur due to solid tumors, occurring at a rate of [~]1,500 deaths per day in the US, highlighting a profound and unmet need for new therapies. Solid tumors evade clearance by T cells due to a variety of immunosuppressive properties of the tumor microenvironment. However, this immunosuppression cannot be easily blocked on a global level because systemic activation of the immune system elicits a host of complications. An ideal therapy for solid tumors would act locally to activate the immune response without evoking global adverse effects. Here we present a biodegradable, macroporous scaffold that is implanted adjacent to the tumor and suppresses the main obstacle to cancer immunosurveillance: intratumoral regulatory T cells. The scaffold also promotes the recruitment and activation of T cell effectors into the tumor, resulting in clearance of otherwise aggressive and fatal tumors in mice. Unexpectedly, the local depletion of Tregs results in an "immunological abscopal effect" acting on distant tumors. We demonstrate that this versatile platform can also deliver tumor-antigen-specific T cells directly to the peri-tumoral environment, bypassing difficulties in intravenous delivery including the environmental barriers imposed by the tumors vasculature. By orchestrating multiple local immunomodulatory treatments, this scaffold offers a general approach to engineer T-cell responses to solid tumors without systemic toxicities.

immunology↗

bioRxiv2021

Mesenchymal stem cells carry and transport clusters of cancer cells

Cell clusters that collectively migrate from primary tumors appear to be far more potent in forming distant metastases than single cancer cells. A better understanding of collective cell migration phenomenon and the involvement of different cell types during this process is needed. Here, we utilize a micropatterned surface composed of a thousand of low-adhesive microwells to screen motility of spheroids containing different cell types by analyzing their ability to move from the bottom to the top of the microwells. Mesenchymal stem cells (MSCs) spheroid migration was efficient in contrast to cancer cell only spheroids. In spheroids with both cell types mixed together, MSCs were able to carry the low-motile cancer cells during migration. As the percentage of MSCs increased in the spheroids, more migrating spheroids were detected. Extracellular vesicles secreted by MSCs also contributed to the pro-migratory effect exerted by MSCs. However, the transport of cancer cells was more efficient when MSCs were physically present in the cluster. Similar results were obtained when cell clusters were encapsulated within a micropatterned hydrogel, where collective migration was guided by micropatterned matrix stiffness. These results suggest that stromal cells facilitate the migration of cancer cell clusters, which is contrary to the general belief that malignant cells metastasize independently. SignificanceDuring metastasis, tumor cells may migrate as a cluster, which exhibit higher metastatic capacity compared to single cells. However, whether and how non-cancer cells contained in tumor cluster regulate its migration is not clear. Here, we utilize two unique approaches to study collective tumor cell migration in vitro: first, in low-adhesive microwells and second, in micropatterned hydrogels to analyze migration in 3D microenvironment. Our results indicate that MSCs in tumor cell clusters could play an important role in the dissemination of cancer cells by actively transporting low-motile cancer cells. In addition, MSC-released paracrine factors also increase the motility of tumor cells. These findings reveal a new mechanism of cancer cell migration and may lead to new approaches to suppress metastases.

bioengineering↗

bioRxiv2019

Augmentation of T-cell activation by oscillatory forces and engineered antigen-presenting cells

Activation of T cells by antigen presenting cells allows them to proliferate, produce cytokines, and kill infected or cancerous cells. We and others have shown that T cell receptors receive and in fact require mechanical forces from their own movements and the movements of antigen presenting cells. Emulation of T cell activation in vitro allows for the massive expansion of T cells necessary for clinical applications. In this paper, we studied the impact of augmenting novel artificial antigen presenting cells of various sizes and antigenic signal strength with mechanical, oscillatory movement. We showed that dynamic culture roughly doubles signal strength as compared to conventional, static culture. We demonstrated that tuning the strength of signal to a \"sweet spot\" allows for robust expansion of induced regulatory T cells, which is impeded by approaches that simply maximize activation.

immunology↗

bioRxiv2019

T-cell activation is modulated by the 3D mechanical microenvironment

T cells recognize mechanical forces through a variety of cellular pathways, including mechanical triggering of the T-cell receptor (TCR) and mechanical triggering of the integrin LFA-1. We show here that T cells can recognize forces arising from the rigidity of the microenvironment. We fabricated 3D hydrogels with mechanical stiffness tuned to 4 kPa and 40 kPa and specially engineered be microporous independent of stiffness. We cultured T cells and antigen presenting cells within the matrices and studied activation by flow cytometry and live imaging. We found there was an augmentation of T-cell activation in the context of mechanically stiffer 3D material as compared to the softer material. In contrast, proliferation, activation markers, and migration were all diminished in T cells cultured in the softer material. These results show that T cells can sense their mechanical environment and amplify responses in the context of mechanical stiffness.

immunology↗