Combo Treatment Releases Brake On Antitumor Immune Responses
It has been a long-held dream in immunology to create a cancer vaccine - but the problem with malignant tumors is that they are notoriously good at evading the immune system. One way they are known to do this is by increasing activity of a specialized group of T cells, known as T regulatory cells (Tregs), which suppress immune responses to self-antigens and reduce inflammation.
An HMS team has now shown that when Treg activity is downregulated in mice receiving local tumor treatment, the mice can be cured of a metastatic cancer--apparently via disinhibition of an antitumor immune response. The work is reported in the April 8 Proceedings of the National Academy of Sciences.
The research team, led by Michael Hamblin, HMS associate professor of dermatology at Massachusetts General Hospital, used photodynamic therapy (PDT) to treat mice with a highly metastatic form of cancer. The treatment involves systemic administration of a photosensitive drug that becomes activated when the tumor is exposed to light of an appropriate wavelength. The activation of the drug causes production of reactive oxygen species, which induce apoptosis and necrosis in cancer cells and destroy the tumor blood supply. "People are often treated with PDT for cancer--not normally for metastatic cancer--but in cancer you don't always know whether it's metastasized," said Hamblin.
Over the years there had been scattered reports that PDT not only destroys tumors locally but also evokes antitumor immune responses that target and attack distant metastases. But this effect has been difficult to reproduce. "One of the theories of why people do not always see this is because of Tregs," explained Hamblin.
The HMS team showed that if PDT is combined with a low dose of the chemotherapy agent cyclophosphamide (CY), it can effectively cure metastatic cancer in mice. Furthermore, when T cells were taken from the spleens of cured mice and mixed with the cancer cells, they specifically killed cells from the target tumor in vitro. "Sort of like a vaccine," said Hamblin, "[the treatment] kills the tumor in such a way that you also vaccinate the host against it at the same time."
The team subsequently performed a series of in vitro experiments, which confirmed that the mechanism by which the PDT-CY treatment worked was via inhibition of cancer-induced Treg activation. "No one had really looked into the role of Tregs in PDT-induced immunity. So what this paper shows is that they are important. And if they are present, they can actually diminish the effectiveness of treatment," explained Pawel Mroz, research fellow in dermatology and co-author on the paper.
"This could easily be clinically applied," said Hamblin. "People are treated with PDT for cancer everyday, but often the cancer comes back. So people getting PDT for cancer could also get a regimen with low dose cyclophosphamide; it isn't going to be that much more of a burden."