Good news! Cancer is history (soon)! This seems to be an interesting and very clever approach!
"The immune systems warriors—T cells—can’t kill a cancer they can’t find. That’s where type 1 conventional dendritic (cDC1) cells come in. These cells capture chunks of tumor cells and present them to killer T cells, kind of like offering a bloodhound a scent. Once activated in this way, the T cells can lock onto tumor cells and destroy them. The problem is that the dendritic cells that do this are too few and far between. So, researchers figured out how to convince cancerous cells to behave as cDC1s and betray their own kind.
The team found three genes that are essential for stem cells to become cDC1s. They then loaded these genes into a modified virus that injects them into cancerous cells. While the trick was less effective in mouse cancers than it was in cultured cancer cells, it only took 0.06% transformation to turn the tide against tumors. ..."
From the abstract of the Perspective:
"Cancer is a systemic disease accompanied by altered immune responses. Dendritic cells (DCs) are important regulators of immunity within the tumor microenvironment (TME). This includes capturing proteins from tumor cells and presenting them to T cells, which are subsequently activated and become tumor-killing cells. Therefore, manipulating DCs is a promising strategy for cancer immunotherapy. One subclass of DCs—type 1 conventional DCs (cDC1s)—is particularly important for initiating tumor-eliminating immune responses, but cDC1-based immunotherapies have not yet been deployed in the clinic mainly because of the sparseness of cDC1s in tumors. ... report that cancer cells can be reprogrammed in vivo into immunogenic cDC1-like antigenpresenting cells that can activate T cells and promote antitumor immunity. This approach overcomes the limitations of cDC1 quantity in the TME and paves the way for future DC-based immunotherapies."
From the editor's summary and abstract:
"Editor’s summary
The success of cancer immunotherapy can be limited by mechanisms that tumors develop to evade destruction by the immune system. Tumors can block the activation and obstruct the ability of immune cells (dendritic cells and T lymphocytes) to destroy the tumor, thereby creating an environment that is beneficial for cancer growth. Ascic et al. developed an approach to directly reprogram cancer cells into dendritic cells in vivo by delivering the transcription factors PU.1, IRF8, and BATF3 with an adenoviral vector ... The transcription factors promoted dendritic cell–like functions and enabled the engineered tumor cells to present antigens and mount cancer-specific T cell immune responses. The tumor-to-immune cell “reprogramming” reshaped the tumor microenvironment, triggering tumor regressions and systemic immunity. ...
Abstract
INTRODUCTION
The success of cancer immunotherapy depends on the priming of tumor-specific T cells. However, tumor cells often down-regulate antigen presentation and mount an immunosuppressive microenvironment, which excludes immunogenic antigen-presenting cells from the tumor. These limitations hinder the broad success of cancer immunotherapies, including immune checkpoint blockade. Type 1 conventional dendritic cells (cDC1s), a rare subset of dendritic cells, are key for recruiting and activating cytotoxic T cells, and their presence in tumors correlates with improved survival. Previous studies showed that the transcription factors PU.1, IRF8, and BATF3 (PIB) can directly reprogram fibroblasts or tumor cells into antigen-presenting cDC1-like cells in vitro within 9 days. However, ex vivo cell manipulation and readministration of these reprogrammed cells pose significant challenges for clinical application.
RATIONALE
We hypothesized that the reprogramming of tumor cells into cDC1-like cells could occur entirely in vivo within the tumor microenvironment. This approach would foster T cell activation by leveraging the unique functions of cDC1. Using a combination of syngeneic models, xenografts, and human cancer spheroids from multiple cancer types, we characterized local and systemic immune responses triggered by reprogramming and developed a viral platform for delivering PIB directly to tumors.
RESULTS
In vivo tumor cell reprogramming demonstrated faster kinetics and higher fidelity than in vitro approaches and resulted in tumor-resident cDC1-like cells showing a mature, immunogenic signature. Reprogramming efficiently progressed in human cancer spheroids despite the presence of immunosuppressive cancer-associated fibroblasts, myeloid-derived suppressor cells, or pericytes, leading to T cell activation and tumor cell elimination. In murine immune-competent models, reprogrammed tumor cells recruited and expanded polyclonal cytotoxic and memory T cells within the tumor while reducing exhausted and regulatory populations. The formation of tertiary lymphoid structures containing B, T, and stromal cells was observed, switching the immune response from “cold” to “hot.” Immune remodeling led to tumor regression independently of endogenous cDC1. CD4+ T cells were identified as critical mediators, because their depletion with antibodies abolished the therapeutic response. Furthermore, in vivo reprogramming established tumor-specific systemic immunity and immunological memory in melanoma models with varying profiles of immunogenicity and responsiveness to immune checkpoint blockade. In addition to the monotherapy effects, we observed a marked synergy with anti–programmed cell death protein 1 (anti–PD-1) or anti–cytotoxic T lymphocyte–associated protein 4 (anti–CTLA-4) immunotherapies. We further confirmed that reprogramming <2% of cells was sufficient to trigger tumor regression, supporting the intratumoral delivery of reprogramming factors.
CONCLUSION
Our study demonstrates that in situ delivery of PIB using adenoviral vectors induces the generation of cDC1-like cells within tumors, leading to remodeling of the tumor microenvironment, the formation of tertiary lymphoid structures, and the expansion of polyclonal cytotoxic and memory T cells. This work provides preclinical proof-of-concept for an off-the-shelf, tumor-specific immunotherapy that can orchestrate systemic and durable antitumor immunity"Reprogramming tumor cells to fight cancer (no public access) "Cancer cells reprogrammed into dendritic cells in vivo promote antitumor immunity"
In vivo dendritic cell reprogramming for cancer immunotherapy (no public access)
In vivo reprogramming of tumor cells to dendritic cells.
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