I skimmed an article on a recent experiment which suggested that it was effective to inject induced colon cancer tumors with an attenuated salmonella variant. According to the article, this stimulated an immune response which suppressed metastasis of the cancer. How exactly does this work?


Tumors are commonly infiltrated with lymphocytes, including T cells, macs, DCs and B cells. The crux of the paper is that their attenuated virus secretes TLR ligands (Toll-like receptor) that resulted in an activation of tumor-suppressive M1 macrophages, a concomitant reduction in immune-suppressive M2 macrophage activity, and an influx of immune infiltrate to the tumor.

So M1 macs are activated typically by IFN-y and LPS stimulation, which is typically through TLR4. Their salmonella is attenuated and causes no disease, check one. It's gram-negative and thus has LPS, check two. It's engineered to secrete bacterial flagellin, a TLR5 agonist, check three.

M1 macs secrete IL12, important for polarizing T cells to TH1/TC1 phenotypes that are oncolytic, and IL10 which can elicit anti-tumor immunity though it's reputation is that of an immunosuppressant. M1 macs can also kill tumors of their own accord by producing nitric oxide which is cytotoxic to tumor cells. TLR4 agonsim on it's own accord also activates T cells in an NF-kB-dependent manner.

Whats also interesting is the inflammatory signal actuated by the macrophages actually tells other immune cells "hey come check this out," and potentially makes for a more robust anti-tumor response. The idea is that inflamed tissues secrete signalling or chemotactic molecules called chemokines which are picked up by chemokine receptors on leukocytes, telling them to enter the zone of infection (and thus the malignancy).

You'll also find, however, that despite immunological advances, modulating cells is a challenge due to the nature of each type of cancer's TME (tumor microenvironment). And so in your paper they tested it in a murine system in bladder cancer, but will it work in a human melanoma must be qualified, for example.


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