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Commentary
Open Access | 
10.1172/JCI188018
Type 2 immunity to the rescue: enhancing antitumor immunity for skin cancer prevention
Matthew D. Vesely1 and Sean R. Christensen1,2
1Department of Dermatology, and
2Department of Surgery, Division of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
Address correspondence to: Sean R. Christensen, Yale Dermatologic Surgery, 40 Temple Street, Suite 5A, New Haven, Connecticut 06510, USA. Phone: 203.785.3466; Email: sean.christensen@yale.edu
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1Department of Dermatology, and
2Department of Surgery, Division of Plastic and Reconstructive Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
Address correspondence to: Sean R. Christensen, Yale Dermatologic Surgery, 40 Temple Street, Suite 5A, New Haven, Connecticut 06510, USA. Phone: 203.785.3466; Email: sean.christensen@yale.edu
Find articles by Christensen, S. in: JCI | PubMed | Google Scholar
Published January 2, 2025 - More info
J Clin Invest. 2025;135(1):e188018. https://doi.org/10.1172/JCI188018.
© 2025 Vesely, et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Abstract
The continuous rise in skin cancer incidence highlights an imperative for improved skin cancer prevention. Topical calcipotriol-plus–5-fluorouracil (calcipotriol-plus–5-FU) immunotherapy effectively eliminates precancerous skin lesions and prevents squamous cell carcinoma (SCC) in patients. However, its mechanism of action remains unclear. Herein, we demonstrate that calcipotriol-plus–5-FU immunotherapy induces T helper type 2 (Th2) immunity, eliminating premalignant keratinocytes in humans. CD4+ Th2 cells were required and were sufficient downstream of thymic stromal lymphopoietin cytokine induction by calcipotriol to suppress skin cancer development. Th2-associated cytokines induced IL-24 expression in cancer cells, resulting in toxic autophagy and anoikis followed by apoptosis. Calcipotriol-plus–5-FU immunotherapy was dependent on IL-24 to suppress skin carcinogenesis in vivo. Collectively, our findings establish a critical role for Th2 immunity in cancer immunoprevention and highlight the Th2/IL-24 axis as an innovative target for skin cancer prevention and therapy.
Authors
Tomonori Oka, Sabrina S. Smith, Heehwa G. Son, Truelian Lee, Valeria S. Oliver-Garcia, Mahsa Mortaja, Kathryn E. Trerice, Lily S. Isakoff, Danielle N. Conrad, Marjan Azin, Neel S. Raval, Mary Tabacchi, Luni Emdad, Swadesh K. Das, Paul B. Fisher, Lynn A. Cornelius, Shadmehr Demehri
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Type 2 immunity in cancer immunosurveillance
In the current manuscript, Oka et al. first performed an open-label trial of 5-FU plus calcipotriol twice daily for 6 days in participants with pre- and postbiopsies of AK and adjacent unaffected skin to assess the immune response (9). These experiments confirmed a marked reduction in clinical AK after 5-FU-plus–calcipotriol treatment and identified infiltration of treated AKs with T helper 2 (Th2) cells expressing CD4 and GATA3. Other T cell subsets (Th1, Th17, and regulatory T cells) were not increased in treated AKs, and treated normal skin did not show infiltration of Th2 cells. Interestingly, Oka and authors also performed follow up studies of patients from their original trial after 5–7 years. Residual AKs showed infiltration with GATA3+ Th2 cells and CD103+ resident memory T cells (TRM), suggesting that the immune surveillance persists for years after treatment with 5-FU plus calcipotriol. Using a mouse DMBA-TPA tumorigenesis model, the authors confirmed that Th2 cells were necessary and sufficient for elimination of SCC-like skin lesions. Calcipotriol plus 5-FU was protective against these tumors only in the presence of CD4+ T cells. Protection was lost in IL-4 receptor-deficient mice and rescued by transfer of WT CD4+ T cells.
Calcipotriol application results in the production of thymic stromal lymphopoietin (TSLP), a potent inducer of Th2 responses, in keratinocytes of psoriasis lesions but not normal skin (15). Oka et al. demonstrated that 5-FU-plus–calcipotriol treatment specifically induced TSLP in keratinocytes of AK and SCC, but not in keratinocytes from unaffected skin, providing a mechanistic link between calcipotriol and the Th2 response (9). The authors also performed transcriptomic analysis of gene expression after 5-FU-plus–calcipotriol treatment and found that IL-24 was one of the most upregulated genes in treated AK (9). IL-24, also known as melanoma differentiation associated gene 7 (MDA7), has been reported to selectively induce cell death in a variety of solid tumor types (16). Human SCC cells, but not normal keratinocytes, were susceptible to IL-24–mediated cell death and autophagy in the presence of 5-FU. In addition, expression of IL-24 in SCC cells was induced by exposure to the canonical Th2 cytokine IL-4. Using mouse models of cSCC cancer induction, Oka and authors confirmed that type 2 immunity was critical for skin cancer surveillance. Constitutive expression of TSLP in mouse epidermis protected animals from SCC-like lesions, and expression of the TSLP receptor in CD4+ T cells was required for this protection. IL-24 was also required, as IL-24–deficient mice were not protected from SCC precursor development during calcipotriol-plus–5-FU treatment. Interestingly, calcipotriol-plus–5-FU treatment still induced marked Th2 cell infiltration to skin lesions but failed to prevent carcinogenesis in the absence of IL-24, underscoring that IL-24 is necessary for elimination of premalignant keratinocytes (9).
Taken together, these findings provide a model (Figure 1) in which topical calcipotriol, in the context of cellular injury produced by 5-FU, induces TSLP expression selectively in AK keratinocytes. TSLP then induces differentiation and recruitment of Th2 cells to AK lesions in the skin, a process that is further enhanced by expression of damage signals such as Annexin A1, Calreticulin, and MHC class II in the epidermis. Th2 cells secrete IL-4 and IL-13, which specifically act on malignant or premalignant keratinocytes to induce IL-24 production. IL-24, acting via an autocrine or paracrine mechanism, then synergizes with 5-FU to enhance apoptosis, autophagy, and eliminate tumor cells (9).
Figure 1Topical calcipotriol plus 5-FU stimulates immune surveillance in actinic keratosis and squamous cell carcinoma. Sun-damaged skin harbors areas of normal epidermis mixed with areas of actinic keratosis, composed of transformed keratinocytes with dysregulated proliferation and differentiation, due to UV-induced somatic mutations. Topical calcipotriol induces TSLP production by transformed keratinocytes in actinic keratosis but not in unaffected keratinocytes. TSLP is recognized by T cells in the dermis and stimulates Th2 differentiation. Keratinocyte injury, mediated by the chemotherapeutic agent 5-FU, leads to expression of damage-associated molecular patterns including Annexin A1, Calreticulin, and MHC class II, which further promote T cell activation and proliferation. Activated Th2 cells secrete IL-4 and IL-13, which specifically stimulate transformed keratinocytes to express IL-24. IL-24 acts in an autocrine and paracrine fashion on transformed keratinocytes to enhance apoptosis, autophagy, and general cell death. In addition, ongoing stimulation of dermal T cells facilitates development of resident memory T cells (TRM) in the skin, allowing for long-term immunosurveillance and elimination of squamous cell carcinoma and its precursors.
Type 2 immunity has traditionally been viewed as favoring tumor growth. In contrast, cancer immunosurveillance and the elimination of cancer cells is viewed as predominately mediated by type 1 immunity, including Th1 cells, CD8+ T cells, and IFN-γ. However, recent evidence suggests that Th2 cells may either promote or fight against cancer based on the tissue context (17). For example, Th2 cells were found to promote pancreatic cancer growth (18), while adoptively transferred Th2 cells eliminated myeloma tumors (19). Similar conflicting results are also seen with IL-4 and TSLP. IL-4 signaling promotes protumorigenic myelopoiesis, driving non-small cell lung cancer, and blockade of IL-4R signaling enhanced cancer immunotherapy (20). In contrast, recombinant IL-4 potentiated type 1 immunity to eliminate cancer (21). TSLP has been found to either promote tumor destruction or tumor growth (22). Ultimately, the cancer subtype, tumor microenvironment, and immune contexture likely determine type 2 immunity’s role in cancer. Taken together, the effect of type 2 immunity on cancer is difficult to predict even in similar tissues. While Oka et al. (9) demonstrate that TSLP production from keratinocytes reduces cSCC formation, a recent study showed that keratinocyte-derived TSLP promoted melanoma growth and metastasis (23).
As with other type 2 cytokines, IL-24 has pleiotropic effects including anticancer properties and propagation of autoimmunity, including allergic diseases (24). Expression of IL-24 in chimeric antigen receptor T (CAR-T) cell therapy improved anticancer efficacy (25). In line with other reports, IL-24 and type 2 immunity, more broadly, are critical for barrier tissue (e.g., skin) function and repair (26). How IL-24 promotes keratinocyte proliferation in chronic inflammatory disease like atopic dermatitis and keratinocyte death in premalignant lesions remains to be determined.
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ISSN: 0021-9738 (print), 1558-8238 (online)