What Causes Relapse After Cancer Immunotherapy?

Tumor-initiating stem cells may be the crux of how immune checkpoint pathways are activated

orange and blue cells

Empowering the human body’s immune system to fight off cancer, a tactic known as immunotherapy has improved outcomes for patients. 

But, there is a lingering problem with immunotherapy, as with many other cancer treatments, which is a relapse. In many cases, the tumor comes back, and doctors don’t know why. 

Immunotherapy is a type of biological therapy, which is a type of treatment that uses substances made from living organisms to treat cancer, says the NIH. 

New research from the lab of Elaine Fuchs, Rockefeller’s Rebecca C. Lancefield Professor, identifies the tumor cells responsible for thwarting the immunotherapy treatment and offers new insights into how they do it. 

In a recent non-human study described in Cell, scientists generated mice with a type of squamous cell carcinoma cancer that responds well to immunotherapy. 

Using this model, the researchers discovered that a subset of cancer cells known as tumor-initiating stem cells survive the treatment by producing a molecule called CD80, which sits on the cells’ surface and dampens the effectiveness of the body’s immune cells that would otherwise attack and eradicate the cancer. 

Probing this mechanism, these researchers discovered that during malignancy, tumor-initiating stem cells (tSCs) selectively acquire CD80. Moreover, upon engaging cytotoxic T lymphocyte antigen-4 (CTLA4), CD80-expressing tSCs directly dampen cytotoxic T cell activity. 

Conversely, upon CTLA4- or TGF-β-blocking immunotherapies or Cd 80 ablation, tSCs become vulnerable, diminishing tumor relapse after ACT treatment.

“Tumor-initiating stem cells make up less than 2 percent of a tumor’s mass, but they’re sneaky. They essentially quiet the immune system to avoid elimination, then later regrow a whole new tumor,” said these scientists in a press release. 

Dr. Fuchs’ team also identified the molecular switch that triggers these cells to make CD80 in the first place, a protein called TGF beta, suggesting potential new avenues for the improvement of immunotherapy. 

For example, antibodies blocking TGF beta could potentially be used in combination with conventional immunotherapy drugs to overcome the resistance problem.   

These researchers concluded saying, ‘these findings place tSCs at the crux of how immune checkpoint pathways are activated.’ 

Rockefeller University is one of the world’s leading biomedical research universities, drawing top scientists and graduate students from around the world in pursuit of one mission: to conduct science for the benefit of humanity.

No conflicts of interest were disclosed.