Biology subjects

Catena, X.

Publications and source records attributed to Catena, X..

3 recordsLinked to original sources

bioRxiv2024

A cancer immunotherapy modality based on dendritic cell reprogramming in vivo

Immunotherapy leads to long-term survival of cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established long-term systemic immunity in different mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for first-in-human trials and other applications of immune cell reprogramming in vivo. One-Sentence SummaryReprogramming of tumor cells to cDC1-like cells in vivo elicits systemic and long-term antitumor immunity.

immunology↗

bioRxiv2024

Blocking MIF secretion enhances CAR T-cell efficacy against neuroblastoma

While chimeric antigen receptor (CAR) T-cell therapies are showing highly promising first results in neuroblastoma, immunosuppressive tumor microenvironments (TME) limit T cell persistence and durable clinical efficacy. To improve CAR T-cell efficacy further, we applied a multi-omics approach including single-cell RNA sequencing and proteomics, which identified 13 targetable immunosuppressive factors in neuroblastoma. Of these, macrophage migration inhibitory factor (MIF) and midkine (MDK) were validated across multiple published RNA datasets. Moreover, they were secreted in high abundance by neuroblastoma tumoroids. Functional validation experiments revealed MIF as a potent inhibitor of CAR T-cells, in vitro and in vivo. Degradation of MIF by PROTAC technology significantly enhanced CAR T-cell activation targeting GPC2 and B7-H3, providing a potential intervention against MIF. By defining the immunosuppressive effects of neuroblastomas TME on CAR T-cell efficacy, particularly the pivotal role of MIF, we provide a therapeutic strategy for improving adoptive cell therapies for this pediatric malignancy.

cancer biology↗

bioRxiv2022

Systemic effects of melanoma-secreted MIDKINE in the inhibition of dendritic cell differentiation and function

Cutaneous melanomas are a prime example of potentially immunogenic tumors, and as such, ideal targets for immune therapy. These lesions have the largest mutational burden described to date, and accumulate a broad spectrum of post-transcriptional and translational alterations that could conceptually result in a plethora of neoantigens for immune recognition. However, a significant fraction of metastatic melanoma patients is or becomes resistant to current immunotherapeutic agents. How lesions that should represent an inherently hot milieu for immune attack shift into immunologically cold or irresponsive neoplasms is not well understood. Combining cellular systems, mouse models and clinical datasets, here we identify the growth factor Midkine (MDK) as a multipronged blocker of antigen presentation. Mechanistically, we found MDK to repress all main aspects of the maturation, activation and function of dendritic cells, particularly of conventional type 1 (cDC1). These roles of MDK were found to involve primary tumors and lymph nodes, and were traced back to suppressive effects on myeloid precursor cells in the bone marrow. Moreover, MDK shifted the transcriptional profile of DCs towards a tolerogenic state that prevented and bypassed CD8+ T cell activation. Blocking MDK enhanced the response to DC-based vaccination and improved the response to immune checkpoint blockade.Together, these data provide insight into how melanomas overcome immune surveillance and support MDK as a target for therapeutic intervention.

cancer biology↗