TLR5 Ligand–Secreting T Cells Reshape the Tumor Microenvironment and Enhance Antitumor Activity

Abstract

The tumor microenvironment counters antitumor T cell responses in part by blunting their activation and infiltration. Ligands that engage Toll-like receptors (TLR) on T cells and antigen-presenting cells can act as potent immune adjuvants. In this study, we show how tumor-reactive T cells engineered to secrete bacterial flagellin, a TLR5 ligand (TLR5L), can engender a co-stimulatory signal that augments antitumor activity. Human T cells engineered to express TLR5L along with DMF5, a T cell receptor that recognizes the melanoma antigen MART-127-35 (DMF5TLR5L T cells), displayed increased proliferation, cytokine production and cytolytic activity against melanoma cells. In a xenogenetic model, adoptive transfer of DMF5TLR5L T cells reduced tumor growth kinetics and prolonged mouse survival. In a syngeneic model, similarly engineered melanoma-reactive T cells (pmelTLR5L) displayed a relative increase in antitumor activity against established tumors, compared to unmodified T cells. In this model, we documented increased T cell infiltration associated with increased levels of CCR1 and CXCR3 levels on T cells, a reduction in PD1+Lag3+ T cells and CD11+Gr1+ myeloid-derived suppressor cells, and changes in the chemokine/cytokine profile of tumors. Our findings show how T cell-mediated delivery of a TLR agonist to the tumor site can contribute to antitumor efficacy, in the context of adoptive T cell immunotherapy.

A Synthetic CD8α:MyD88 Coreceptor Enhances CD8+ T-cell Responses to Weakly Immunogenic and Lowly Expressed Tumor Antigens

“…Genes were cloned into the pMIG-w vector containing a GFP reporter gene. Retroviral vector supernatants were produced from Phoenix Ampho and Eco packaging cell lines we have previously described(11). For generating engineered mouse T cells, pmel or OT-I T cells were activated for 48 hrs.…”

LYG1 exerts antitumor function through promoting the activation, proliferation, and function of CD4+ T cells

“…rhLYG1-induced upregulation in the expression of chemokines within tumors is associated with increased T-cell infiltration and antitumor response, which is consistent with the previous studies. 30,31 Our data showed that LYG1 could increase the chemokine secretion in the tumor microenvironment.…”

Toll-like receptor stimulation in cancer: A pro- and anti-tumor double-edged sword

“…Such stimulation decreased tumor volume in models of breast cancer , colorectal cancer (Rhee et al, 2008), lung cancer (Burdelya et al, 2012;Zhou et al, 2012), and T-and B-cell lymphoma (Leigh et al, 2014), mainly mediated by increased tumor necrosis and neutrophil infiltration Rhee et al, 2008;Zhou et al, 2012). In addition, in a melanoma mouse model, T cells engineered to constitutively produce TLR5 ligand could increase anti-tumor activity by increasing proliferation and cytolytic activity of these T cells against melanoma cells (Geng et al, 2015). Finally, in a cohort of patients with non-small-cell lung cancer (NSCLC), TLR5 overexpression was associated with good prognosis.…”