New research reveals how calcipotriol-plus–5-FU therapy activates immune pathways to prevent squamous cell carcinoma with long-lasting protection.
Study: T helper 2 cell–directed immunotherapy eliminates precancerous skin lesions. Image Credit: Me dia/Shutterstock.com
Skin cancer rates are increasing globally, driving research into new protective treatments. One promising approach is topical immunotherapy with calcipotriol plus 5-fluorouracil (5-FU), which effectively eliminates precancerous skin lesions.
A recent study published in the Journal of Clinical Immunology sheds light on the biological mechanisms behind this therapy.
Immunotherapy for skin cancer
Immunotherapy for cancer is a groundbreaking and effective approach but is often prohibitively expensive and associated with severe side effects. These challenges have spurred research into more affordable and less toxic therapies.
Skin squamous cell carcinoma (SCC), the second most common type of skin cancer, is vulnerable to immune responses even at its precancerous stage. Actinic keratosis (AK), a known risk factor for SCC, can be treated to reduce the risk of progression.
Current AK treatments include topical 5-fluorouracil (5-FU), photodynamic therapy, imiquimod, and tirbanibulin. However, only 5-FU has shown a short-term reduction in SCC risk, which disappears within two years.
This limitation has driven interest in AK immunotherapy as an "innovative and attainable strategy." Previous research demonstrated that topical calcipotriol combined with 5-FU is highly effective in eliminating AKs, but it lacked insight into its mechanism.
Calcipotriol, a vitamin D analog used to treat psoriasis, increases thymic stromal lymphopoietin (TSLP) levels in keratinocytes. When paired with 5-FU, this effect is amplified, leading to a significant infiltration of T cells into AK lesions. This process generates tissue-resident memory T cells (TRM), providing long-term immune defense.
Calcipotriol-plus–5-FU has been shown to reduce SCC rates over three years without causing widespread cytotoxic effects. The current study aims to unravel the specific biological pathways that drive this promising therapeutic action.
About the study
The study included 18 patients with AKs who were treated topically with 0.0025% calcipotriol-plus–2.5% 5-FU twice daily for six days. The diagnoses before and after treatment were confirmed by clinical as well as skin biopsy evaluation.
Biopsies were taken before treatment, one day, and eight weeks following the treatment. The results showed deep redness developing around the AKs post-treatment. The erythema was resolved by week 8.
AKs reduced in number by 95% on the face, clearing completely in 70% of the participants, and by 82% on the scalp. On the upper limbs, AKs were reduced by 65% and 68% on the right and left, respectively.
Th2 cell activation
Following the application of calcipotriol-plus–5-FU, there was an increase in AK infiltration by CD4+ Th2 cells, which spared normal skin, however. This was accompanied by increased numbers of TRM cells, confirming the induction of mainly Th2 cells.
Calcipotriol induces cytokine production in the form of increased TSLP, immune stimuli like damage-associated molecular patterns (DAMPs), and human leukocyte antigen class II (HLA-II) within the premalignant keratinocytes, again sparing normal skin. The TSLP-induced Th2 polarization of CD4+ T cells is essential for the efficacy of this therapy.
The Th2/IL-24 axis
The increase in TSLP triggers CD4+ Th2 cells to produce interleukin-24 (IL-24), which eliminates cells by causing toxic processes like autophagy (self-digestion) and anoikis (loss of cell adhesion).
IL-24 also boosts enzymes like MMP-1, leading to the separation of the epidermis from the underlying membrane, ultimately resulting in cell death through apoptosis.
This Th2-driven immune response is key to how immunotherapy prevents cancer. Remarkably, the T-cell immunity generated by this treatment lasts over five years, continuing to protect against SCC by targeting AKs.
CD4+ T cells are critical to this effect, as they activate TSLP without needing CD8+ T cells or B cells. In a mouse model, removing CD4+ T cells negated the benefits of calcipotriol-plus–5-FU therapy.
Neither calcipotriol nor 5-FU alone were as effective as their combination in reducing tumor growth or delaying cancer onset, underscoring the importance of their synergy.
Conclusions
The findings reveal for the first time that Th2 polarization, triggered by calcipotriol-plus–5-FU immunotherapy, is effective in preventing cancers. This highlights the Th2/IL-24 pathway as a promising new target for cancer therapies.
IL-24 was shown to act as a key effector molecule, inducing toxic autophagy and apoptosis in cancer cells both within and outside the tumor environment. This dual action results in direct and “bystander” antitumor effects, amplifying its therapeutic potential.
As CD4+ T cells play a central role in adaptive immunity, their activation against tumor antigens can help address early-stage carcinomas and precancerous changes. The long-lasting protection provided by this topical immunotherapy, driven by TSLP induction, underscores its ability to delay and prevent squamous cell carcinoma (SCC).
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