Rosa Barreira DaSilva, Ph.D., Senior Scientist, Cancer Immunology, Genetech
Chemokine Modifying Enzymes Could Help Cancer Immunotherapies Work Better
Genentech researchers say enzymes that modify chemokines - the proteins that attract immune cells to tumors - could help immunotherapies be effective for more cancer patients.
The immune response to cancer is complex. The first stage is antigen capture by dendritic cells. These antigens are used to make peptides that can bind to major histocompatibility complex (MHC) proteins found on the surface of cancerous cells.
The binding of peptides to MHCs activates T cells, which in turn prompts other immune cells to migrate to the tumour site where they exert their cytotoxic activity.
Migration is the key to the whole system and the proteins that control it – chemokines – are a therapeutic opportunity says Rosa Barreira DaSilva, senior scientist at Genentech, who shared the details of her research at the Antibody Engineering and Therapeutics conference.
“The migration of primed lymphocytes such as CD88 T-cells from the lymph nodes into the tumour is aided by one very well-known chemokine called cxcl10.
“It is an interferon-induced chemokine, which binds to the chemokine receptor cxcr3 [which is] up regulated in activated lymphocytes and indeed the presence of a tumour induces expression of this kind of chemo attractant.”
Targets
In theory, there should be enough cxcl10 to induce immune cells to migrate. But, DaSilva says, in some cancers, cxcl10 does not function correctly.
“There are many cases where T-cells are either excluded or not present at all in the tumor environments and patients are refractory to immunotherapy…So all this clinical evidence prompted us to study if chemokines could be regulated,” she said.
Initially Genentech focused on an extracellular enzyme called hypeptidylopeptidase - also known as DPP4 or CD26 - which truncates small proteins that contain either of the amino acids proline or alanine at their N terminus. This includes the chemokine cxcl10.
“In the case of cxcl10 truncation abrogates its chemo attractive activity. So both human and mouse truncated cxl10 are not able to induce migration of cxcr3 expressing T cells.”
Other chemokines also have proline or alanine residues, meaning they can also be modified and lose their ability to induce migration according to DaSilva.
“This finding promoted us to study the hypothesis that modulation of post-translational modification could influence leukocyte migration into tumours.”
DPP4 inhibitors
To test the theory the team gave DPP4 inhibitors – which are approved for diabetes - to laboratory mice. They found that treated animals produced more full-length form cxl10, which induced migration of cxcr3 expressing lymphocytes into tumors.
The preclinical findings are supported by data from clinical trials.
DaSilva said, “We initiated different clinical trials to evaluate DPP 4 inhibitors either as monotherapy or in combination with immunotherapy (anti-PDL1).”
The researchers looked at two other enzymes called QPCT and QPCTL--which also modify chemokines – specifically the chemokines CCL2 and CCL7. They found that QPCT and QPCTL induced changes that protect the chemokines against truncation by DPP4.
Further research showed that, while both types of enzymes are active in vitro, the extracellular version – QPCTL – is more active in vivo.
Therapeutic Opportunities
The research suggests both DPP4 and QPCTL are promising therapeutic targets.
DaSilva said, “We have been studying these post translational modifications for quite a long time and they almost balance each other, and you know, depending on the chemokine or the cell that you want to study you need to think a little bit about which strategy to Utilize.
“We believe that dpp4 Inhibitors could be placed in tumours devoid of T-cells to help strengthen the cxcl1 gradients and help bring those CD9t cells into the core of the tumour.
“QPCTL inhibitors could be placed maybe in indications where there is already an inflamed environment where there are CD8 T cells but there is also immunosuppression.”
