Why immunotherapy works for some cancer patients and not others

Immunotherapy, a biological therapy that improves the immune system's ability to recognize and attack mutated tumor cells, has changed the treatment landscape
for cancer patients.
Cancer is caused by the gradual accumulation of
DNA mutations.
However, many patients do not respond
to immunotherapy.
For example, in highly mutated colorectal and endometrial cancers, studies have shown that only half respond to immunotherapy
.

On October 27, researchers at Yale University School of Medicine published a new study in the journal Cancer Discovery, a journal of the American Association for Cancer Research, that found a possible explanation for
this happening.
In an analysis of a phase 2 clinical trial of the immunotherapy drug pembrolizumab in 24 patients with endometrial cancer, the Yale team found that the specific mechanism of DNA repair defects in tumors was a key determinant of
patient outcomes.

"We wanted to understand why some patients respond better to immunotherapy than others," said
co-corresponding author Ryan Chow, MD/PhD.
Candidate
to work in the Department of Genetics and the Institute of Systems Biology at Yale University.

In the study, the Yale team focused on the failure of a process known as "mismatch fix
.
" When cells divide, errors
often occur in DNA.
Through mismatch repair, a special set of proteins recognizes and corrects errors
in DNA.
However, this editing process is disrupted in many different types of cancer, resulting in high levels of mutations
.

The research team was led
by Professor Zhou, an ophthalmic resident, and former MD/PhD Dr.
Eric Song.
A student at Yale University and a professor of obstetrics, gynaecology and reproductive sciences, Dr.
Alessandro Santin, noticed that mismatch repair defects can be caused
by two different mechanisms.
One is that the DNA repair mechanism itself is mutated, resulting in the production of defective repair proteins; In the second case, the production of DNA repair mechanisms stops
completely.
In both cases, tumors accumulate very high levels of mutations that promise to make them good candidates for immunotherapy
.

"An analogy is a dysfunctional toy factory," Zhou said
.
"Maybe the factory makes broken toys, or the factory doesn't have people and stops making toys
altogether.
" Either way, children won't be happy
.
”

However, the researchers found that tumors with defective DNA repair proteins responded significantly better to immunotherapy than those with inhibited production of DNA repair
proteins.
Ultimately, they say, these differences can be traced back to changes
in the immune response to both types of tumors.

"When it comes to immunotherapy, it seems that the process — in this case, the underlying cause of the mismatch repair defect — may be as important as the endpoint," Chow said
.

Song added: "The innovative use of clinical trial data can guide us in understanding how immunotherapy manipulates the immune system and ultimately improves the way
we treat patients.
"

Santin is a member of the Yale Cancer Center, while Song is a resident at Smailo Cancer Hospital
.

Journal Reference:

1. Ryan D.
   Chow, Tai Michaels, Stefania Bellone, Tobias MP.
   Hartwich, Elena Bonazzoli, Akiko Iwasaki, Eric Song, Alessandro D.
   Santin.
   Distinct mechanisms of mismatch repair deficiency delineate two modes ofresponse to PD-1 immunotherapy in endometrial carcinoma.
   Cancer Discovery, 2022; DOI: 10.
   1158/2159-8290.
   CD-22-0686