Expanding cross-presenting dendritic cells enhances oncolytic virotherapy and is critical for long-term anti-tumor immunity

Abstract

Immunotherapies directly enhancing anti-tumor CD8+ T cell responses have yielded measurable but limited success, highlighting the need for alternatives. Anti-tumor T cell responses critically depend on antigen presenting dendritic cells (DC), and enhancing mobilization, antigen loading and activation of these cells represent an attractive possibility to potentiate T cell based therapies. Here we show that expansion of DCs by Flt3L administration impacts in situ vaccination with oncolytic Newcastle Disease Virus (NDV). Mechanistically, NDV activates DCs and sensitizes them to dying tumor cells through upregulation of dead-cell receptors and synergizes with Flt3L to promote anti-tumor CD8+ T cell cross-priming. In vivo, Flt3L-NDV in situ vaccination induces parallel amplification of virus- and tumor-specific T cells, including CD8+ T cells reactive to newly-described neoepitopes, promoting long-term tumor control. Cross-presenting conventional Type 1 DCs are indispensable for the anti-tumor, but not anti-viral, T cell response, and type I IFN-dependent CD4+ Th1 effector cells contribute to optimal anti-tumor immunity. These data demonstrate that mobilizing DCs to increase tumor antigen cross-presentation improves oncolytic virotherapy and that neoepitope-specific T cells can be induced without individualized, ex vivo manufactured vaccines.

Biomimetic Nanophotosensitizer Amplifies Immunogenic Pyroptosis and Triggers Synergistic Cancer Therapy

“…DCs as antigen‐presenting cells, are the “sentinels” of anti‐tumor immunity. [ 43 ] Detecting the maturation of DCs is one of the main immunological process factors. Compared with other groups, the proportion of maturated DCs (CD45 + CD11c + CD80 + CD86 + cells) in tumors and tumor‐draining lymph nodes (TDLNs) of “M‐Cu‐T + L” group was highest (Figure 7b and Figure S18a, Supporting Information), indicating that “M‐Cu‐T + L” could effectively promote the mature of DCs to exercise immune function.…”

Immune responses elicited by ssRNA(-) oncolytic viruses in the host and in the tumor microenvironment

“…The approval of Adstiladrin represents an important milestone in the use of viruses to treat cancer, officially extending their applicability in the clinic as Vectors for gene therapy, and opening the way to other replication-deficient recombinant OVs (rOVs) platforms to be reconsidered for this clinical application. Gene therapy is not the only therapeutic discipline in which OVs' irruption improves treatment possibilities and outcomes: OVs have been shown to be a good match for CAR-T cells-based therapies, improving its responses in solid tumors through TME remodeling and/or maximizing T cell functions [155][156][157][158] . Local delivery of some therapeutic OVs, such as NDV, has demonstrated their suitability for In situ cancer vaccination, leading to complete durable responses without the need to identify neoantigens beforehand [39,[159][160][161] .…”

Cytotoxicity as a form of immunogenic cell death leading to efficient tumor antigen cross‐priming

“…Advancing our knowledge of all these processes may permit translation into innovative therapeutic interventions such as raising cDC1 numbers using sFLT3L in combination with immunotherapy strategies 31,33,34,38,45,87–89 . Moreover, perhaps by mimicking or enforcing cytotoxicity in part of the tumor lesions, we could generate endogenous vaccines.…”