Extranodal induction of therapeutic immunity in the tumor microenvironment after intratumoral delivery of Tbet gene-modified dendritic cells

Abstract

Murine dendritic cells (DC) transduced to express the Type-1 transactivator T-bet (i.e. mDC.Tbet) and delivered intratumorally (i.t.) as a therapy are superior to control wild-type DC in slowing the growth of established subcutaneous (s.c.) MCA205 sarcomas in vivo. Optimal anti-tumor efficacy of mDC.Tbet-based gene therapy was dependent on host NK cells and CD8+ T cells, and required mDC.Tbet expression of MHC class I molecules, but was independent of the capacity of the injected mDC.Tbet to produce pro-inflammatory cytokines (IL-12 family members or IFN-γ) or to migrate to tumor-draining lymph nodes (TDLN) based on CCR7 ligand chemokine recruitment. Conditional (CD11c-DTR) or genetic (BATF3−/−) deficiency in host antigen crosspresenting DC did not diminish the therapeutic action of i.t.-delivered wild-type mDC.Tbet. Interestingly, we observed that i.t delivery of mDC.Tbet (versus control mDC.Null) promoted the acute infiltration of NK cells and naïve CD45RB+ T cells into the tumor microenvironment (TME) in association with elevated expression of NK- and T cell-recruiting chemokines by mDC.Tbet. When taken together, our data support a paradigm for extranodal (cross)priming of therapeutic Type-1 immunity in the TME after i.t. delivery of mDC.Tbet-based gene therapy.

Tertiary lymphoid structures in the era of cancer immunotherapy

“…Delivery of DCs engineered to express the T cellspecific T box transcription factor T-bet into sarcoma tumour lesions (MCA205 xenografts) of mice promotes lymphocyte infiltration, T H 1 cell skewing and the development of TLSs and slows tumour growth 124,125 . This process is IL-36γ-dependent, as this therapeutic strategy fails when given to wild-type mice that are coadministered an IL-36 receptor antagonist or when given to IL-36-deficient mice 125 .…”

Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8+ effector T cell responses

“…Indeed, this has been reported previously for Tbet-engineered DC injected directly into established tumor lesions in mice. 42 Recent evidence suggests that extranodal T cell priming in ectopic or tertiary lymphoid organs correlates with better overall survival of cancer-bearing patients. 43,44 Therefore, we must be open to the likelihood that it is not necessary for injected DC to migrate to secondary lymph nodes in order to effectively prime tumor-specific T cell responses that yield therapeutic benefit.…”

Biosynthesis and Functional Significance of Peripheral Node Addressin in Cancer-Associated TLO

“…Following intratumoral injection of Type 1-polarized DC (DC engineered to overexpress Tbet, i.e., DC.Tbet) into established murine sarcomas or colon carcinomas, CD4 + and CD8 + T cell recruitment to the TME is observed within 2 days, with an upregulation of PNAd expression detected by 5 days after treatment. This suggests that PNAd-independent events control early T cell recruitment to the TME, and that T cell-dependent factors may consequently result in PNAd upregulation on tumor-associated VEC ( 28 , 29 ). Once established, PNAd + vessels become surrounded by dense infiltrates of both CD11c + DC and CD3 + T cells, with these non-classical TLO principally localized near the tumor periphery for at least 2 weeks following initial therapeutic intervention ( 28 , 29 ).…”