A type of white blood cell that typically helps coordinate the immune response can also destroy tumor cells, indicating that it could open up new options for people who don’t respond to traditional cancer immunotherapy treatments.

When the researchers pitted individual CD4 T cells, also known as helper T cells, and tumor cells extracted from melanoma patients against each other, they found that about one-third of the helper T cells had the ability to kill the cancer cells. The team reported its findings in a study published Friday in Science Advances.

“The idea not of using chemotherapy but exploiting our own immune system has changed the treatment of patients in the last 10 years, and so now we are really seeing how to further implement this,” says Camilla Jandus, an assistant professor of pathology and immunology at the University of Geneva and last author of the new paper.

Many immunotherapy treatments rely on a kind of white blood cell called CD8 T cells. Also known as killer T cells, these immune cells are specialized to eliminate cells that have become infected or cancerous. Generally, helper T cells assist by secreting molecules that influence the activity of other immune cells.

Researchers have found evidence that these helpers can also kill cells that have succumbed to malaria or viruses such as dengue. However, “It was not yet clearly demonstrated — particularly in humans — that these cells are directly able to engage with the target cells and kill it in cancer,” Jandus said.

She and her colleagues collected CD4 T cells, focusing on those that could recognize antigens from cancer cells, from blood and tissue samples taken from 33 people with melanoma. Drawing from a subset of the samples, the researchers then placed a single T cell and tumor cell together in each well of a nanochip that contained more than 21,000 tiny wells. The T cells were dyed blue, while the tumor cells were orange. The researchers also placed a dye in the wells that turned cells green as they perished. The team then observed the chip over a period of 24 hours.

“As we saw a green event popping up, it would mean that tumor cell was killed,” Jandus says. “We could define the timing of killing and how many wells had a killing event, and with this we could determine that approximately one-third of our CD4 [T cells] were successfully able to target and kill the tumor.”

The researchers observed that it took CD4 T cells around 5.3 hours to kill their foe, compared with about 2.4 hours on average for CD8 T cells. The team also found that the CD4 T cells had to come into contact with the tumor cells in order to vanquish them.

Through the nanochip experiment as well as other "less sophisticated" ones, Jandus and her colleagues were able to find CD4 T cells with the ability to kill cancer cells in samples from every patient they examined, although the amount varied in different people.

Additionally, the researchers identified several molecules that seemed to play a role in defeating tumor cells. One, called granzyme B, is also released by CD8 T cells when they encounter tumors. It causes the tumor cell to go into apoptosis, or programmed cell death. The victorious CD4 T cells also carried a protein known as SLAMF7 on their surface, which helps the cell release granzyme B and related molecules.

One limitation of the new findings is that the scientists examined T cells from a small number of participants. The team is now expanding the research to include cells from people with other kinds of tumors, as well as investigating which other molecules produced by the CD4 T cells may play a role in destroying cancer cells. 

“We know that the CD8 T cell targeting [immunotherapy] is not sufficient to eliminate tumors in many patients, unfortunately,” Jandus said. “Knowing that we have here a second weapon that we can exploit to target those tumors that don’t respond to CD8-based treatments is, for sure, encouraging.”

The article, “Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer,” was published Feb. 26 in Science Advances. The authors of the study were Amélie Cachot, Margaux Saillard, Georg Alexander Rockinger, Philippe Guillaume, Julien Schmidt, Raphaël Genolet, George Coukos, Alexandre Harari, Daniel E. Speiser and Pedro Romero, University of Lausanne; Mariia Bilous, Tania Wyss and David Gfeller, University of Lausanne and Swiss Institute of Bioinformatics; Yen-Cheng Liu, Xiaokang Li and Hatice Altug, École Polytechnique Fédérale de Lausanne; Walter Reith, University of Geneva; Mara Cenerenti, Giuseppe Ercolano and Camilla Jandus, University of Geneva and Ludwig Institute for Cancer Research, Lausanne Branch; Maria Pia Protti, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute; Kalliopi Ioannidou and Laurence de Leval, Lausanne University Hospital and University of Lausanne; Joseph A. Trapani, Peter MacCallum Cancer Centre; and Alexander Mathis, Harvard University and Swiss Federal Institute of Technology.