Scientists at MUSC Hollings Cancer Center have pinpointed a pathway by which triple-negative breast cancer (TNBC) cells cease to respond to immunotherapy and have evaluated a new approach to address that issue. The therapy, which is described in the journal Cell Reports, shows that the combination treatment can reactivate the effect of immunotherapy in a preclinical model of TNBC.
TNBC represents between 10 and 20% of all breast cancer and it is considered as invasive with relatively low five-year survival rate in comparison to other subtypes of the illness. TNBC is known to occur in younger women with black women being the most affected. It is known as ‘triple-negative’ because the cells themselves are negative for three receptors—the estrogen, progesterone, and HER2—on which usual breast cancer treatment usually operate. Consequently, few treatment options are available for the patients with TNBC, especially if the tumor has progressed to the advanced or metastatic stage.
Immune therapy especially, checkpoint inhibitors such as pembrolizumab has significantly transformed cancer therapy especially for people with blood cancer. Nonetheless, solid tumors, including TNBC, have elicited rather a weak response. For such patients with metastatic TNBC, pembrolizumab is effective only for those with TNBC tumour cells that strongly overexpress the PD-L1 protein. PD-L1 binds to PD-1 on the immune T-cells and thus protects cancer cells from being targeted by the immune system. Checkpoint inhibitors achieve this by preventing this interaction hence allowing the immune system attack the tumor.
The Ogretmen Lab is interested in sphingolipids – a category of fat molecules that play a role in maintaining cell membrane integrity. Of these sphingolipids one is ceramide which is synthesized by the ceramide synthase 4 (CERS4). It is shown that tumor cell ceramides are important for stabilizing the cell membranes so that proteins such as PD-L1 are retained on the cell surface to be recognized by immunotherapy.
It also came to the knowledge of the research team that when the levels of CERS4 are low, ceramides decrease and make the cell membrane unstable and as a consequence, PD-L1 has to pull back from the outer membrane of the cancer cell. After internalization PD-L1 becomes inaccessible to immunotherapeutic agents and at the same time activates pathways associated with metastasis, which otherwise makes immunotherapy futile. This insight then revealed how TNBC cells are able to become resistant to treatment that was being administered to them.
To counteract this resistance, the team came up with a two-part treatment approach that would solve the problem. They employed together with a PD-L1 inhibitor and another anti-tumor drug that inactivates the metastatic signal, which is activated once PD-L1 is internalised. In a mouse model of TNBC in which CERS4 was deleted, this combined treatment prevented membrane defortexification, anchored PD-L1 on the cell surface, and made the tumor reinstitute immunotherapy again.
In the preclinical trials the PD-L1 inhibitor or the anti-metastatic drug when given singularly did not have any appreciable effect on tumor formation. But when combined, the researchers noted that this treatment effectively reduced the size of the tumors and in some cases caused the tumors to regress. Lead author Wyatt Wofford and Dr. Ogretmen, who led this study, specifically pointed out that such combined modality might help THEMIs overcome immunotherapy resistance.
While the current anti-metastatic drug being used in the study is not suitable for clinical use, the team is on the lookout for new compounds, including FDA approved drugs, that inhibit the same metastatic pathway. These endeavors are meant to establish sustainable combination therapies that can be experimented into clinical trials for the TNBC patients.
As of now, there has been some progress in identifying potential combinations that could advance to the clinic, said Ogretmen about another aggressive type of the disease.
Reference
Wyatt Wofford et al, Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response, Cell Reports (2024).
