Study Finds Novel Mechanism of Resistance to Immunotherapy Targeting HER2

A new study has discovered how cancer cells escape death by lymphocytes through the disruption of interferon-gamma signaling, according to results published Nature Communications. The findings show promise in potentiating future immune-based therapies against solid tumors, according to the study authors.

As immunotherapies continue to show promise in more effectively combating several tumor types, many current strategies focus on ensuring the efficient delivery of active cytotoxic cells directly to tumors. It is thought that once the lymphocytes engage with cancer cells, they will reliably destroy them, provided that inhibitory mechanisms are in check, according to the study authors.

"While these immune-based approaches have already been approved for the treatment of some hematologic malignancies, they fail to show efficacy in clinical studies with solid tumors. This failure has previously been associated with the incapacity of T cells to successfully target cancer cells directly,” said corresponding study author Joaquín Arribas, co-program director of Preclinical and Translational Research at Vall D’Hebron Institute of Oncology, in a press release. “Up until now, little has been reported on the mechanisms adopted by tumors which enable them to resist T-cell attack. This has been the focus of our present research.”

Arribas added that several different strategies are now being implemented by the cancer research community to overcome these mechanisms of resistance.

“We aimed to go one step further by establishing whether more mechanisms exist that enable cancer cells to overcome the onslaught of targeted lymphocytes,” Arribas said in a press release.

Using human epidermal growth factor receptor 2 (HER2)-driven cell lines and patient-derived zeongraphs, and T cell bispecific antibodies and chimeric antigen receptor targeting HER2, the research revealed a novel mechanism of resistance to redirected T cells. Specifically, the study authors found that even when active cytotoxic cells are successfully delivered to tumor cells, the latter adopt a strategy to avoid their elimination by lymphocytes. The findings suggest that the disruption of interferon-gamma signaling confers resistance and therefore promotes disease progression, according to the study authors.

"Interferon gamma acts as an interrupter that controls cell death. Certain cancer cells learn to switch off this pathway and thus survive the attack of lymphocytes,” said study author Enrique J. Arenas, in a press release. “At present, there is no easy way of applying this discovery in clinical practice. Namely, to effectively identify those patients who have this pathway turned off. This represents a next step in our research; to develop a simple method to be able to do so.”

Previous studies showed that the p95HER2-T-cell bispecific antibody can successfully guide lymphocytes directly to cancer cells for their targeted killing. This direct delivery was achieved thanks to the p95HER2 protein, which is only located in tumor cells. This novel immune-based approach can be used to tackle certain HER2-positive breast cancers through its exclusive targeting of cancerous cells, according to the study authors.

“Driven by our discoveries, we aim to more precisely screen patients for enrollment in this clinical study, better predict when resistance will occur, and develop strategies to overcome the mechanisms that govern this resistance," Arribas said in a press release.

REFERENCE

The unveiling of a novel mechanism of resistance to immunotherapy targeting HER2. EurekAlert! https://www.eurekalert.org/pub_releases/2021-02/vdio-tuo022321.php. Published February 23, 2021. Accessed February 25, 2021.