New Strategies to Boost Immunotherapy Response in Pancreatic Cancer and Melanoma

Researchers have identified multiple new approaches to improve immunotherapy responses in hard-to-treat cancers, including pancreatic cancer and melanoma, according to recent studies.

At the University of Texas MD Anderson Cancer Center, researchers have identified an epigenetic target called DPY30 that could sensitize pancreatic tumors to immunotherapy and serve as a predictive biomarker for patients most likely to benefit from treatment. The study, published in Cancer Research, was led by researchers in Genomic Medicine, Cancer Biology, and the former chief scientific officer.

DPY30 is part of a group of proteins called the COMPASS complex, which helps control which genes are turned on or off by modifying how DNA is packaged inside cells. The researchers discovered that DPY30 also directs the activity of this complex at DNA replication forks — critical sites where DNA is copied. When DNA replication is disrupted, which is common in cancer cells, DPY30 helps protect these stressed replication forks, supporting cancer cell survival and continued growth.

Conversely, loss or depletion of DPY30 destabilizes replication forks, leading to increased genomic instability and the activation of inflammatory signaling pathways. This promotes immune cell infiltration into tumors and supports the development of long-term antitumor immunity, effectively converting previously immunologically "cold" tumors into more responsive, "hot" tumors that are sensitized to immune checkpoint blockade.

Patient samples of pancreatic cancer with higher levels of DPY30 tend to have higher tumor grades, a poorer prognosis and an inferior response to immunotherapy. Therefore, DPY30 could serve as a potential predictive biomarker to stratify patients most likely to benefit from treatment. Further evaluation is needed before this can be applied to clinical trials.

Separately, researchers at the University of California San Diego have discovered a treatment approach for pancreatic cancer that redirects the body's pre-existing immune response to cytomegalovirus (CMV) toward pancreatic tumors, slowing tumor growth and improving survival in preclinical models. The findings were published in the Journal of ImmunoTherapy for Cancer.

The treatment works by injecting CMV-derived peptides directly into the bloodstream, activating memory T cells that recognize the CMV peptides from a previous infection. When these peptides are present in the tumor, CMV-specific T cells can infiltrate and kill the tumor cells. More than 80% of the world's population is infected with CMV, and approximately 10% of all circulating CD4 and CD8 T cells are CMV-specific.

In preclinical studies, mice treated with the therapy had a median survival of 42 days compared with 25 days among untreated mice — a significant 68% improvement in survival. At 18 days post-implantation, tumors treated with the therapy were significantly smaller than untreated tumors. The treatment promoted preferential accumulation of CMV-specific T cells within pancreatic tumors and increased tumor apoptosis. Once the dose was lowered, the treatment was well tolerated and no toxicity was observed.

The research is still in the early stages and further work is needed before it can be translated to human studies. The team plans to characterize approximately 200 newly discovered human CMV T-cell epitopes for translating the therapy to the clinic.

In melanoma research, a molecular biologist at Fred Hutch Cancer Center will investigate new ways to boost immunotherapy responses in metastatic melanoma patients, supported by a $270,000, two-year grant from the American Cancer Society. The research will explore how the tumor microenvironment helps cancer cells evade the innate immune system, focusing on a novel form of tumor immune evasion involving type 2 conventional dendritic cells (cDC2). The goal is to identify novel pathways that regulate protective immune responses to cancer that can be exploited via new therapies.

Immunotherapy has joined surgery, radiation and chemotherapy as a major pillar of cancer treatment, with response rates of 37% in melanoma and higher in select colorectal cancers. However, only around 30% of patients respond to this type of treatment overall, and immunotherapy has had limited success in pancreatic cancer due to the aggressive nature of these tumors combined with a low mutational burden and an immunosuppressive tumor microenvironment.