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Systemic immunity Is required for effective cancer immunotherapy

Spitzer, Carmi, & Reticker-Flynn et al. Cell (2017)

Put “X” in, and “Y” works. Take “X” out, and “Y” doesn’t work. That means “X” is essential for “Y.”

That simple formulation is at the heart of many great scientific studies. 

And that’s what Teiko cofounder Matthew Spitzer did in this seminal Cell 2017 paper.

Put the “peripheral immune system in,” and immunotherapy worked. Take the “peripheral immune system out,” and the immunotherapy failed. That means the “peripheral immune system” is essential for immunotherapy to work. Seems obvious right? You need a peripheral immune system for immunotherapy to work. But scientists for a while have thought that the immune system at the tumor just needed a jolting awake. This paper demonstrated that the peripheral immune system outside the tumor, from the peripheral blood, played a critical role.

Put the “peripheral immune system in,” and immunotherapy worked. Take the “peripheral immune system out,” and the immunotherapy failed.

That leads to the question: how on earth can you take a peripheral immune system out?

Well, in mice, you can apply a drug called FTY720. This kind of drug traps immune cells in the lymph nodes. That means the immune cells of mice who get FTY720 can’t send out their immune cells through the blood.

Now, here’s the interesting part.

Matt and team took mice with colorectal cancer (the MC38 model):

  • One group of mice were given a checkpoint inhibitor drug to treat the cancer 
  • Another group of mice were given a checkpoint inhibitor drug and FTY720

What happened?

In the mice who got the checkpoint inhibitor drug alone, the tumors grew more slowly. In the mice who got the checkpoint drug and FTY720, the tumor grew uncontrollably, and the mice died.

That’s a real difference. In the mice that benefited from treatment, the immune cells that were activated in the lymph node were allowed to flow through the blood to the tumor. No traffic flow of cells through the blood, no benefit from treatment. That means the peripheral immune system is essential for immunotherapy to work.

Reference citation: Spitzer MH, Carmi Y, Reticker-Flynn NE, Kwek SS, Madhireddy D, Martins MM, Gherardini PF, Prestwood TR, Chabon J, Bendall SC, Fong L, Nolan GP, Engleman EG. Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell. 2017 Jan 26;168(3):487-502.e15. doi: 10.1016/j.cell.2016.12.022.

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Illustration. In the center is a grey mass labeled "tumor" under a magnifying glass. Inside the tumor are three grey cells all with "zzz" above them. Outside the magnifying glass (and therefore outside the tumor) in the four corners are different depictions. Top left shows three red cells and is labeled "novel T cell clones". Top right shows a lymph node with red T cell zones and the words "LN trafficking required". Bottom right shows two red T cells in a blood vessel labeled "LAG-3 and CD8+" with the words "peripheral biomarkers". Bottom left shows a spleen with the same grey, sleeping T cells. There's a red lightning bolt and the words "impaired systemic immune response in cancer".

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Although most research focuses on tumor-killing immune cells at the site of the tumor, new research increasingly demonstrates the value of studying circulating immune cells in peripheral blood to identify new therapeutic targets to enhance tumor-killing immune responses. We highlight recent publications with peripheral blood biomarkers and discuss recommendations for how to incorporate peripheral blood immune profiling into your drug development pipeline.