Harnessing the immune response against common moles to combat melanoma

Scientists at Massachusetts General Hospital suggested that activating CD4+ T cells (white) at common moles could be a strategy to prevent noncancerous melanocytes (red and green) from progressing to melanoma. (Erik Schiferle)

About a third of melanomas begin with benign moles. Now, researchers at Massachusetts General Hospital have found an immune mechanism for these noncancerous skin cells that they believe could be leveraged to treat melanoma or prevent its recurrence.

Common moles are naturally targeted by the immune system's CD4+ T cells and would be eliminated if it weren’t for immunosuppressive cells known as regulatory T cells, or Tregs, the team explained in a new study published in Science Advances.

Overcoming this immune tolerance by activating CD4+ T cells could serve as a novel strategy for developing drugs to prevent progression to melanoma in high-risk populations or to help existing immunotherapies treat the skin cancer, the researchers suggested.

Compared with melanoma—which consists of malignant cells—common moles, also known as melanocytic nevi, carry a very small number of mutations. Although moles have far fewer T cells and antigen-presenting cells in their microenvironment, they do seem to possess an immune surveillance mechanism that controls the lesions.

To determine how the immune system works on benign melanocytic nevi, the MGH team transplanted human samples onto mice that lacked immune systems. Surprisingly, 82% of the transplanted nevi disappeared by themselves, while surrounding skin remained intact, the researchers found.

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In the models, the team detected a significant accumulation of CD4+ T cells that were carried over from the human host. The timing of the rejection of the moles also coincided with the expansion of the T cells.

Treating mice with a T-cell-suppressing agent called cyclosporine prevented the regression. 

Normally, T-cell activities are controlled by Tregs, which typically lose their immunosuppressive function when moved from humans to this type of mouse model. The researchers treated some mice with human IL-2, which can promote Treg development. While on treatment, five of six IL-2-treated nevus mouse models remained stable. But the moles went into regression after IL-2 was stopped, the team found.

The researchers then implanted human melanoma cells into the skin graft sites on the mice that had rejected the benign moles in the hopes of determining whether T-cell immunity can protect against cancer.

 Tumor growth and metastasis were significantly reduced. Three animals with stable mole grafts didn’t experience any protection from melanoma, the team reported.

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Many research groups have zeroed in on Tregs to combat different types of cancer. A team led by Sanford Burnham Prebys Medical Discovery Institute showed inhibiting a protein called Siah2 could rein in Tregs and make melanoma sensitive to PD-1 blockers.

The findings from the current Science Advances study suggested that “if you could block the Tregs that already exist in human moles, you could reactivate the anti-melanocyte CD4+ T cells to eliminate the mole while cross-protecting the patient against the melanoma developing and/or reappearing,” first author Erik Schiferle explained in a statement.

Future endeavors could focus on developing localized or topical treatments to suppress the Tregs at the site of the mole, Schiferle added. Such a treatment could activate local CD4+ T cells to protect people with benign moles that are at high risk of progressing to cancerous cells, and it could enhance the body’s antitumor response and boost other therapies, including PD-1 inhibitors, the team said.