T cells are normally able to attack cancer cells (shown here), but new research finds that residual malignant cells can subvert T cells' vigilance.
The new research was a collaborative effort among scientists at the Institute of Cancer Research in London, the Leeds Institute of Cancer and Pathology, and the University of Surrey in Guildford — all of which are in the United Kingdom — and researchers from the Mayo Clinic in Rochester, MN.
The Mayo Clinic's Tim Kottke is the first author of the study, and the findings have been published in the journal Cancer Immunology Research.
Kottke and his colleagues set out to investigate why cancer recurs after many years of tumor latency. As the authors explain, understanding and preventing this phenomenon is highly important because usually, when the cancer recurs, it does so unpredictably and more aggressively than the first time.
This happens because the cancer becomes resistant to treatment. As the authors note, knowing how the recurrent tumors differ from the initial ones, as well as what triggers them, would enable clinicians to intervene in a more timely and effective manner.
How cancer cells subvert the immune cells
To gain a better understanding of these aspects, Kottke and colleagues designed a mouse model of cancer dormancy.
After treating mice that had cancer with chemotherapy, the rodents seemed cured for between 40 and 150 days. However, after a longer follow-up period, some of them "developed late, aggressive local recurrences, mimicking the clinical situation in multiple tumor types."
After performing several experiments in vivo and in cell cultures, the researchers put this relapse down to the "subversion" of two main elements of the immune system: the so-called TNF-alpha chemical, and natural killer (NK) cells.
First and foremost, they showed that after treatment, the residual cancer cells subverted the TNF-alpha chemical signal by turning it from an anti-tumor, immune-supporting agent into a growth factor for the disease.
Secondly, they unraveled the mechanism that weakens the surveillance abilities of both T cells and NK immune cells.
The scientists found that resistant malignant cells are covered with a large amount of a molecule called PD-L1, which, in turn, interacts with another molecule called PD-1 on immune cells, "instructing" the T cells not to attack.
So, Kottke and his team gave the mice a PD-1 or TNF-alpha inhibitor intravenously and found that "long-term treatment [...] effectively slowed, or prevented, recurrence."
Immunotherapy could 'block' relapse
Study co-author Alan Melcher, a professor of translational immunotherapy at the Institute of Cancer Research, comments on the findings, saying, "Our study finds the body's own immune system seems to play a crucial role when cancer relapses."
"The immune system goes from keeping cancer cells in check to awakening and feeding residual cells, while turning a blind eye to their growth."
Prof. Alan Melcher
"Excitingly," he continues, "many of the methods employed by treatment-resistant tumors to regrow and hide from the immune system can be blocked using existing immunotherapies."
"This idea is, in fact, supported by emerging data from clinical trials, showing that immunotherapies can reduce the risk of cancers coming back," explains Prof. Melcher.
Study co-author Kevin Harrington, who is a professor of biological cancer therapies at the same institute, also weighs in. "It is becoming [increasingly] clear that the immune system is at the core of the puzzle of how we can treat cancer more effectively," he says.
"This fascinating new study," adds Prof. Harrington, "helps explain why sometimes a patient's immune system can be effective against cancer cells while at other times it is not."
"Changes must occur in these [cancer] cells that make them better able to manipulate the immune system — and understanding this could open up new treatment options to prevent relapse," Prof. Harrington concludes.