Abstract
The potential of bacteria-mediated tumor therapy (BMTT) is highlighted by more than a century of investigation. Attenuated Salmonella has prevailed as promising therapeutic agents. For BMTT - categorized as an immune therapy - the exact contribution of particular immune reactions to the therapeutic effect remains ambiguous. In addition, one could argue for or against the requirement of bacterial viability and tumor targeting. Herein we evaluate the isolated therapeutic efficacy of purified LPS and TNF-α, which together account for a dominant immunogenic pathway of gram negative bacteria like Salmonella. We show that therapeutic efficacy against CT26 tumors does not require bacterial viability. Analogous to viable Salmonella SL7207, tumor regression by a specific CD8+ T cell response can be induced by purified LPS or recombinant TNF-α (rTNF-α). Conversely, therapeutic effects against RenCa tumors were abrogated upon bacterial avitalization and limited using isolated adjuvants. This argues for an alternative mechanistic explanation for SL7207 against RenCa that depends on viability and persistence. Unable to boost bacterial therapies by co-injection of rTNF-α suggested therapeutic effects along this axis are exhausted by the intrinsic adjuvanticity of bacteria alone. However, the importance of TNF-α for BMTT was highlighted by its support of tumor invasion and colonization in concert with lower infective doses of Salmonella. In consideration, bacterial therapeutic effectiveness along the axis of LPS and TNF-α appears limited, and does not offer the necessary plasticity for different tumors. This emphasizes a need for recombinant strengthening and vehicular exploitation to accommodate potency, plasticity and distinctiveness in BMTT.
Highlights
Tumor therapy using bacteria represents a concept with a long standing tradition [1]
Endpoint tumor volumes did not display significant differences in either model upon co-injection of TNF-α (Figure 7D, 7E). These results were transferrable to Rag1−/− mice. These results suggest that effector mechanisms induced by TNF-α at the therapeutic phase of bacteria-mediated tumor therapy (BMTT) may already be driven to its limit by the bacteria alone and that no additional effect can be achieved when recombinant TNF-α is applied in combination with the bacteria
This study aimed to determine if tumor-therapeutic effects against CT26 and renal carcinoma (RenCa) described for SL7207 can be induced via avitalized bacteria, LPS or recombinant TNF-α, likely accounting for the dominant adjuvant pathway of gram-negative bacteria
Summary
Tumor therapy using bacteria represents a concept with a long standing tradition [1]. Infection with various bacterial agents, alone or in combination, became an early strategy to counteract tumor growth [2, 3]. Coley deployed strategies of local application and/ or heat killing of bacteria to control infection while hoping to retain the therapeutic effect. He made an early observation of a correlation between fever induction and a positive response [4].
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