The intriguing case of a man with melanoma tumors that responded in different ways to the same checkpoint-blocking drug has yielded an important clue to the causes of resistance to immunotherapy treatments, according to Dana-Farber researchers. The findings could help guide the use of immunotherapy in individual patients.
The 74-year-old patient, described in a report in Cancer Discovery, had melanoma that had metastasized, sending cancer cells throughout the body and forming new tumors. His doctors prescribed pembrolizumab, a PD-1 immune checkpoint blocker, which unleashes the body’s immune forces against the tumors, and has been highly effective in some patients with advanced melanoma.
The researchers, led by Rizwan Haq, MD, PhD, note that immunotherapies, which have gained a central role in cancer therapy in the past few years, have “dramatically varied responses among different patients, or even among different tumors in the same patient.” The factors underlying these varied responses aren’t well understood and teasing out those factors is a major goal of the immunotherapy research field.
An illuminating case
This patient with metastatic melanoma proved to be particularly interesting: The PD-1 blocker pembrolizumab prompted such a powerful attack by the man’s immune system that within 11 months, the tumors had disappeared — except for a single tumor on his adrenal gland that did not respond at all to the drug. This raised the question: What was different about this tumor that enabled it to escape the immune response triggered by the pembrolizumab? If the researchers could spot the difference, it might shed new light on cancer’s resistance to immune checkpoint blocker drugs.
The investigators’ strategy was to compare the genetic profile of the patient’s tumors that had responded to the pembrolizumab to the genetic profile of the single tumor that had resisted the drug. They performed whole-exome sequencing on a biopsy sample of the original tumor (which was sensitive to the drug) and on a biopsy sample of the resistant tumor.
Comparing the two genetic profiles, they found that the genomes of the original and the resistant tumors contained similar numbers of DNA mutations. But eventually they identified an important way in which the genomes differed. One of the mutations in the resistant tumor disabled the function of a known tumor-suppressor gene, FBXW7, while in the original, drug-sensitive cancer, FBXW7 was intact. Therefore, the scientists inferred, the loss of the FBXW7 gene might be what caused the resistant tumor’s ability to evade the immune system, and normal function of FBXW7 in a tumor might be necessary for the cancer to respond to PD-1 immune blockers.
To test this idea, the researchers deleted FBXW7 function in cells and in experimental animal models of melanoma. Sure enough, the studies showed that tumors lacking FBXW7 function were resistant to anti-PD-1 immunotherapy treatment. In addition, animals with tumors that lacked FBXW7 function had poorer survival. This, the authors say, for the first time “establishes a role for the tumor suppressor gene FBXW7 in anti-tumor immunity.”
Still to be determined, though, was how the loss of FBXW7 in tumor cells led to the failure of immune checkpoint inhibitor therapy. What the researchers discovered was that in the absence of FBXW7, the tumors lost their ability to respond to double-stranded RNA, which ordinarily triggers immune responses to viruses.
“It will be of therapeutic interest to comprehensively understand the mechanisms by which the activation of viral sensing pathways promotes tumor immunity,” the authors say. “The findings provide further rationale for combining immune checkpoint blockade therapy with selected double-strand DNA or double strand RNA agonists to overcome resistance to immunotherapy in genomically defined cancer patient populations.”