Neutrophils are cells of your innate immune system. That is, they are the first responders to any injury and pathogen insult to your tissues. And solid tumors, well you can think of them as chronic overhealing wounds; And neutrophils respond and get localised in tumor microenvironment, just like they do at site of injury. But can neutrophils be manipulated to kill the cancer cells?

A neutrophil
Source - Blausen.com staff (2014). "Medical gallery of Blausen Medical 2014". WikiJournal of Medicine 1 (2). DOI:10.15347/wjm/2014.010. ISSN 2002-4436
Author: BruceBlaus
CC BY-SA 4.0

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There has been a long standing debate in the field that whether neutrophils are pro or anti-tumor. Finally, a middle ground solution for this was suggested by Powell and Huttenlocher. According to them based on the signals that polarize the neutrophils, they can act as both pro and anti-tumor. This started a hunt for finding ways to target tumors by making best of anti-tumor effects of neutrophils. This is where the new drug, LY500307, comes in.

Targetting estrogen receptor to suppress tumor growth.

Recently, Zhao and colleagues from a university in China were surprised by efficacy of LY500307 against some tumors in-vivo(in the living animal). However, if they they treated these cells on a tissue culture dish, nothing ever happened, and they wondered.

They wordered how, they wondered why, yesterday they dreamt about patent and cites. But all they could see is just another Lemon Tree.

Anyway, so they started tearing apart the mechanism. Now, the interesting part is that LY500307 is an agnoist for Estrogen-Beta receptor(aka ERβ). It was initially developed by Eli Lilly for treatment of schizophrenia, but it seem to be effective against some tumors, as well. If you are familiar with sturcture of estrogens, you will notice that LY500307 is quite similar to Estrogens. So no wonder it binds to estrogen receptors in cells. Estrogen receptors are proteins in the cells that get activated when they bind to estrogen. Their activation makes cells do things, depending on which cells detects estrogen. For instance if it was a epithelial cell in nipple it would differentate to mammary gland cell. If it was a follicle cell in ovary it would regulate ovulation.

However, it has been shown that there are isoforms of Estrogen receptors in our cells, ERα and ERβ receptors. ERα has been shown to be pro tumor while ERβ has been activation has been shown to suppress the tumor growth. Guess which one is the drug in question likes more? Yes, ERβ. Which is why authors were interested in this drug anyway to begin with.

The drug makes tumor cells secrete molecules that attract immune cells.

But this supression of tumor was not because activation of ERβ somehow killed tumor cells. What activated ERβ did was that it made these tumor cells to make inflammatory cytokines(the molecules made by our cells, that attract other immune cells to site of secretion). And one of those cytokines was Interlukin 1 beta(aka IL1-β). This cytokine is a potent recruiter of neutrophils to the site of secretion.

So they took mice with triple negative breast cancer tumors. Triple negative tumors are tumors which are not dependent on estrogen, progesterone or epidermal growth factor for their growth. So hormonal treatment don't work on these tumors and they are agressive. But when these mice were given the new drug their tumors secreted IL1-β which caused infiltration of neutrophils into the tumor microenvironment. And the rest is history. They confirmed this by showing that the mice which lacked a gene for IL1-β, did not recruit neutrophils and their tumors did not respond to this drug.

So it looks like IL1-β secretion from tumor cells, via this drug, is one way of recruiting and polarizing anti-tumor neutrophils. Though I would say that further study is required given opposing roles of neutrophils in cancer. But I completely think that this study is worth sharing. I mean, if we can use small molecules to recruit cancer fighting immune cells, instead of biologicals, or CAR-T, or CAR-NK cells, it could make immunotherapy for cancer, way more affordable.

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References

Powell DR, Huttenlocher A. Neutrophils in the Tumor Microenvironment. Trends Immunol. 2016 Jan;37(1):41-52. doi: 10.1016/j.it.2015.11.008. Epub 2015 Dec 14. Review. PubMed PMID: 26700397; PubMed Central PMCID: PMC4707100

Erteberel or LY500307

Zhao L, Huang S, Mei S, Yang Z, Xu L, Zhou N, Yang Q, Shen Q, Wang W, Le X, Lau WB, Lau B, Wang X, Yi T, Zhao X, Wei Y, Warner M, Gustafsson JÅ, Zhou S.
Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis. Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):E3673-E3681. doi: 10.1073/pnas.1803291115. Epub 2018 Mar 28. PubMed PMID: 29592953; PubMed Central PMCID: PMC5910874.

ERα and ERβ receptors.

triple negative breast cancer

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Signing off
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