How Amgen and AstraZeneca's asthma drug Tezspire holds promise for colorectal cancer

Chronic inflammation may give rise to cancer cells in multiple organs. And regulatory T cells, or Tregs, play an important role in supporting tumor growth by suppressing an anti-tumor immune response. Now, scientists at the Benaroya Research Institute (BRI) have linked the two troublemakers together in pinpointing a potential new drug target for colorectal cancer.

A subgroup of Tregs expressing the receptor for the inflammatory protein thymic stromal lymphopoietin (TSLP) may hold the key to the progression of colorectal cancer, the BRI team showed in mice.

In a new study published in Science Translational Medicine, the researchers showed a TSLP-targeted antibody inhibited colorectal tumors in two mouse models.

In December, the FDA approved Amgen and AstraZeneca’s anti-TSLP antibody Tezspire, or tezepelumab, to treat asthma. So treating colorectal cancer with an anti-TSLP antibody drug could potentially be translated to humans as well, the BRI team suggests.

TSLP is a cytokine produced primarily by surface cells at barrier tissues, including the colon. In a Nature Immunology study in 2018, some of the BRI scientists found that TSLP promotes the survival of mouse breast cancer cells.

“We got into this work because we saw TSLP played an important role in breast cancer and we wondered if there were other cancers it might be involved with,” Steven Ziegler, Ph.D., senior author of both studies, said in a statement.

The expression of TSLP in the colon was indeed increased in mouse colorectal tumors, the BRI researchers found. High expression of TSLP in tumors also correlated with severe colorectal cancer in human patients, the team noted from six independent databases.

Simultaneously, a subset of Tregs expressing TSLP’s receptor were preferentially recruited to colons after the development of colorectal cancer in mice, the team found, while these Tregs were largely absent in adjacent normal colons. Similarly, the researchers found these Tregs were also significantly increased in the tumor samples and peripheral blood of human colorectal cancer patients.

Besides the receptor of TSLP, these Tregs also expressed the interleukin-33 receptor, or ST2. But unlike TSLP, genetically deleting ST2 on Tregs didn’t have any significant effect on the number and size of tumors compared to control mice after chemical induction of colorectal cancer in the animals.

The researchers then administered an anti-TSLP neutralizing antibody in two mouse models of colorectal cancer. The treatment shrank tumors just as those TSLP receptor-expressing Tregs diminished in the colon.

Cancer immunotherapies such as Merck & Co.’s Keytruda and Bristol Myers Squibb’s Opdivo have been approved to treat colorectal cancer but only for a small fraction of patients with microsatellite instability-high or mismatch repair deficient tumors.

Hoping to improve upon immuno-oncology agents, a team at the Dresden University of Technology in Germany recently found that inhibiting the B7H4 and B7H3 proteins could be a promising strategy in slowing or even shrinking colon cancer.

Scientists at Memorial Sloan Kettering Cancer Center proposed that inhibiting the protein ENPP1 could make tumors more visible to the immune system. In a mouse model of colorectal cancer, the team showed that removing ENPP1 could improve the response to checkpoint inhibitors.

Now, the findings on TSLP may provide a new avenue for developing therapies against colorectal cancer, and TSLP blockade may be a treatment strategy worth further investigation for the disease, Ziegler said.

Pointing to Tezspire as “an approved drug” that can block the cytokine, Ziegler said the team is now “seeing there’s an opportunity to use it in other indications like colon cancer.”