Mobilizing antibodies to take on cancer

Scientists at the Weizmann Institute are paving the way toward an immunotherapy that will exploit a different, previously unused immune system weapon against cancer: naturally produced antibodies. Their results were published in Cell in March 2022.

Antibodies are proteins manufactured by a class of immune cells, known as B lymphocytes, to neutralize specific threats. Says Prof. Ziv Shulman of the Department of Systems Immunology, “We’ve now shown that the immune systems of cancer patients can produce antibodies against tumors.” Prof. Shulman headed the project together with Prof. Irit Sagi of the Department of Immunology and Regenerative Biology.

“These natural antibodies appear to have an unrealized therapeutic potential,” Prof. Sagi says. “More research is needed in order to apply them in future therapies or as diagnosis reagents.”

In the past few years, naturally occurring antibodies have commonly been found in cancerous tumors, but their purpose was unknown. Indirect evidence, however, had suggested that they do provide some sort of antitumor benefit: Patients who survived longer and were more responsive to anticancer drugs were found to have higher concentrations of the antibody-producing B cells in their tumors. Still, there was no way of determining whether these cells, and the antibodies they made, contributed to improved survival, and if so, how they accomplished that feat.

To explore this question, Prof. Shulman and Dr. Roei D. Mazor, a physician, joined forces with Prof. Sagi, whose lab has expertise in creating cellular models of invasive cancers. Dr. Mazor brought samples of ovarian tumors that had been surgically removed from several dozen women, provided by Prof. Ram Eitan of the Rabin Medical Center.

Dr. Mazor and Weizmann scientists identified a molecule that is targeted by the newly identified antibodies: an enzyme called MMP14 (MT1-MMP), a membrane-bound protease. In cancer, this enzyme operates in the tumor’s microenvironment and gets out of control, cutting through the matrix around the cancer cells and helping them invade surrounding tissue and metastasize. The researchers found that the ovarian tumors in their study contained abnormally high levels of the MMP14 enzyme.

In attacking this enzyme, some of the antibodies had accumulated mutations that improved their fit to the tumor, and specifically, to this enzyme.

These findings open up a new approach to developing cancer immunotherapies – one that will make use of natural antitumor antibodies. Although the study focused on ovarian cancer patients, the findings are relevant to additional cancer types.

Prof. Ziv Shulman’s research is supported by the Azrieli Foundation; Miel de Botton; the Moross Integrated Cancer Center; and the Rising Tide Foundation.

Prof. Irit Sagi’s research is supported by the Azrieli Foundation, and the Rose Family Fund for Crohn’s and Colitis Research. Prof. Sagi is the incumbent of the Maurizio Pontecorvo Professorial Chair.