Targeting primary and metastatic tumor growth in an aggressive breast cancer by engineered tryptophan auxotrophic Salmonella Typhimurium

Abstract

The global cancer burden is growing and accounted for 10 million deaths in 2020. The resurgence of chemo- and radiation resistance have contributed to the treatment failures in many cancer types. Therefore, alternative strategies are desired for the effective cancer therapy. Bacteria-mediated cancer therapy presents an attarctive alternative option for the treatment and diagnosis of cancers. Herein, we describe an engineered Salmonella Typhimurium (ST) auxotrophic for tryptophan as a cancer therapeutic. The tryptophan auxotrophy was sufficient to render ST avirulent and highly safe to mice. The auxotroph recovered from the infected tumors had improved ability to target and colonize the tumors. We show that tryptophan auxotrophy reduced the fitness of ST in healthy tissues, but not in the tumors. We evaluated the auxotroph in highly aggressive metastatic 4T1 breast cancer model to inhibit primary tumor growth and lung metastases. The therapy greatly suppressed the primary growth with tumor-free survival of 40% mice. Importantly, therapy abolished the metastatic dissemination of tumor to lungs. Further, therapy markedly diminished the macrophage population in the tumors that may have contributed to the therapeutic benefit recorded. Collectively, results highlight the therapeutic efficacy of the tryptophan auxotrophic ST in an aggressive metastatic cancer model.