Chemotherapy May Promote Resistance To Immunotherapy In Pancreatic Cancer, Study Shows

Immunotherapy has been a very important treatment in recent years, with many patients in lung cancer, malignant melanoma and many other cancers experiencing dramatic improvements in their prognosis with this cutting-edge therapy. In pancreatic cancer, however, progress in immunotherapy has been slow and its effectiveness has been extremely limited.

Recently, a new study suggests that chemotherapy, which is commonly used in pancreatic cancer, may affect the immune system of patients, reducing the ability of immune cells to attack pancreatic tumours.

The study, led by researchers from the Perlmutter Cancer Center at NYU Langone Medical Center, focused on how T cells in the body's immune system attack tumours after immune checkpoints such as PD-1 are switched off.

The body's immune system normally recognises tumours as abnormal and attacks them, but cancer cells can cunningly hijack immune checkpoints such as PD-1 to shut down the body's immune response. Immune checkpoint inhibitor therapies, which have emerged in recent years, work by turning off these immune checkpoints so that the immune system can once again detect the cancer cells and send immune cells to kill them.

The study was published online on 13 February in the journal Nature Communications. The study analysed 139,000 cells (from 27 patients) from ductal adenocarcinoma of the pancreas, a cancer that is often difficult to detect and treat, with a 5-year survival rate of only 12 per cent. According to the researchers, the tumours shrank dramatically if there was a strong immune response around the tumour tissue (which is crucial).

The new findings show that by comparing patients before chemotherapy (11) and after chemotherapy (6), the molecules used by immune checkpoint inhibitors to block immune checkpoints plummeted by as much as three times. Currently, immunotherapy has not been successful in ductal adenocarcinoma of the pancreas.

The authors of the study say that these new findings may suggest that immunotherapy may be more effective in pancreatic ductal adenocarcinoma by abandoning PD-1-targeted inhibitors and replacing them with novel inhibitors of the TIGHT target.

More importantly, TIGHT is the more common immune checkpoint in pancreatic ductal adenocarcinoma. The study showed that if one switched to a TIGHT immune checkpoint inhibitor, there were 18 times more molecules available for the inhibitor than PD-1 before chemotherapy and as much as five times more after chemotherapy.

"The study shows how chemotherapy can have a profound effect on the tumour microenvironment of pancreatic ductal adenocarcinoma," said the study's co-senior investigator Dr. Aristotelis Tsirigos, a professor of medicine and pathology at New York University Grossman School of Medicine.

"Importantly, our findings suggest that chemotherapy may promote subsequent immunotherapy resistance in pancreatic ductal adenocarcinoma," said the study's co-senior investigator, Dr. Diane Simeone, Laura and Isaac Perlmutter Professor of Surgery at the Perlmutter Cancer Center.

"Further studies are needed to determine whether we want to combine chemotherapy with immunotherapy in the treatment of this stubborn and often fatal cancer because of this potential drug resistance promotion," added Simeone, who is also a professor in the Department of Pathology at NYU Grossman and director of the Pancreatic Cancer Center.

Chemotherapy can also have effects that include a reduction in the number of other cancer-related immune cells, such as fibroblasts and macrophages, which can promote cancer growth if these effects are left unchecked. The researchers note, however, that this remains to be determined further.

"With new technologies that have allowed us to see what is happening in patients at the cellular level, we can adjust our assessment of immunotherapy and better tailor our treatment to what is actually happening around the tumour."