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Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24-mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention.

Hidradenitis suppurativa (HS) is a chronic, heterogeneous inflammatory skin disorder with limited therapeutic options. The immune checkpoint receptor TIGIT is emerging as a regulator of chronic inflammation, yet its role in HS remains unknown. Here, we investigated TIGIT and its ligands in HS using tissue profiling, transcriptomics, and an ex vivo functional explant model. A tissue microarray containing 52 HS, 9 ruptured follicular cysts, and 4 normal skin samples demonstrated significantly increased TIGIT expression in HS lesions. In contrast, the TIGIT ligand PVRL3 was significantly decreased in HS, a finding also observed in a publicly available RNA-seq dataset. Because TIGIT suppresses inflammation only when adequately engaged by its ligands, reduced PVRL3 may impair inhibitory checkpoint signaling in HS. To test whether TIGIT engagement could suppress HS inflammation, we developed an ex vivo explant model using freshly obtained HS lesional tissue. The system was validated using triamcinolone, a corticosteroid, which consistently reduced IL-6 production. Treatment with a TIGIT agonist antibody significantly reduced IL-6 by 72 hours. These findings provide the first functional evidence that TIGIT activation attenuates inflammatory pathways in HS, supporting TIGIT agonism as a potential therapeutic strategy.

Here we report the effects of loss of the Toll-like receptor-associated signaling adaptor myeloid-differentiation factor 88 (MyD88) on tumor induction in two distinct mouse models of carcinogenesis. The 7,12-dimethylbenz[a]anthracene (DMBA)/12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin papilloma model depends on proinflammatory processes, whereas the 3'-methylcholanthrene (MCA) induction of fibrosarcoma has been used by tumor immunologists to illustrate innate and adaptive immune surveillance of cancer. When exposed to a combination of DMBA/TPA, mice lacking MyD88 formed fewer skin papillomas than genetically matched WT controls treated in a similar manner. Unexpectedly, however, fewer MyD88⁻/⁻ mice formed sarcomas than WT controls when exposed to MCA. In contrast, MyD88-deficient mice did not show a defective ability to reject highly immunogenic transplanted tumors, including MCA sarcomas. Despite the reported role of TNF in chronic inflammation, TNF-deficient mice were significantly more susceptible to MCA-induced sarcoma than WT mice. Overall, these data not only confirm the key role that MyD88 plays in promoting tumor development but also demonstrate that inflammation-induced carcinogenesis and cancer immunoediting can indeed occur in the same mouse tumor model.

Abstract The immunological status of human meningiomas is not well understood, hindering the development of rational immunotherapeutic strategies. We measured the levels of PD-L1, PD-L2, and immune cell subsets using multiplex quantitative immunofluorescence in a tissue microarray composed of 73 human meningiomas (56 WHO Grade 1, 13 WHO Grade 2, and 4 WHO Grade 3). We analyzed tumor-infiltrating immune cell populations, T-cell activation/dysfunction, and macrophage phenotypes. PD-L1 and PD-L2 were detected in 5.8% and 68.7% of cases, respectively. There was a higher PD-L1 expression in CD68+ macrophages compared with tumor cells (p < 0.001). There was a weak positive correlation between PD-L1 expression and CD3+ T-cell infiltration. The level of CD3+ cells and T-cell activation/proliferation in human meningiomas were highly variable with an increased CD4-to-CD8 ratio in higher grade tumors (p < 0.05). There was a stronger correlation between GZMB/Ki67 with PD-L2 than PD-L1. We found that 15.23%, 6.66%, and 5.49% of macrophages were CD163+, CD68+, and CD163+CD68+, respectively. In cases where there is high CD3+ T-cell infiltration, 23.5% and 76.5% had dormant and activated T-cell phenotypes, respectively. We conclude that human meningiomas are either PD-L1low TILlow or PD-L1low TILhigh tumors and harbor variable TIL infiltration and phenotypes.

Physical examination revealed extensive, nearly confluent, pink-red plaques associated with tense and flaccid bullae, as well as erosions resulting from ruptured bullae (Figure 1). Linear deposition of IgG and C3 at the dermal-epidermal junction can be shown on direct immunofluorescence, which is the best method for diagnosis of bullous pemphigoid with a sensitivity of 90.8%.2 Detection of circulating autoantibodies against collagen XVII and dystonin-e by enzyme-linked immunosorbent assay may aid in the diagnosis. The Nikolsky sign is usually present.3 SUMMARY TABLE Condition Clinical characteristics Mucosal involvement Nikolsky sign Bullosis diabeticorum Tense bullae on normal-appearing, noninflamed acral sites in patients with diabetes mellitus; asymptomatic lesions Not present Not present Bullous pemphigoid Tense, serous, or hemorrhagic bullae on the trunk and extremities; often associated with pruritic urticarial plaques Not commonly present Not present (positive Asboe-Hansen sign) Pemphigus vulgaris Painful, flaccid bullae with erosions and hemorrhagic crust formation; usually on the face, scalp, trunk, and intertriginous areas Present Present Stevens-Johnson syndrome Pink-red morbilliform rash on the face, trunk, and extremities that progresses to purpuric macules and patches with painful epidermal detachment Present Present

Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on HIF-1, a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our present studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrated a strong cytotoxic signature at the transcript and protein levels, and HIF-1 inhibition abrogated skin and systemic diseases in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell-rich inflammatory infiltrate exhibited increased amounts of HIF-1 and a cytotoxic signature. Granzyme B-expressing T cells were concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.

Severe immune-related adverse events (irAEs) occur in up to 60% of patients with melanoma treated with immune checkpoint inhibitors (ICIs). However, it is unknown whether a common baseline immunological state precedes irAE development. Here we applied mass cytometry by time of flight, single-cell RNA sequencing, single-cell V(D)J sequencing, bulk RNA sequencing and bulk T cell receptor (TCR) sequencing to study peripheral blood samples from patients with melanoma treated with anti-PD-1 monotherapy or anti-PD-1 and anti-CTLA-4 combination ICIs. By analyzing 93 pre- and early on-ICI blood samples and 3 patient cohorts ( n  = 27, 26 and 18), we found that 2 pretreatment factors in circulation—activated CD4 memory T cell abundance and TCR diversity—are associated with severe irAE development regardless of organ system involvement. We also explored on-treatment changes in TCR clonality among patients receiving combination therapy and linked our findings to the severity and timing of irAE onset. These results demonstrate circulating T cell characteristics associated with ICI-induced toxicity, with implications for improved diagnostics and clinical management. Clonally diverse and activated memory CD4 + T cells at baseline are associated with the development of severe immune-related adverse events, irrespective of the affected organ system, in patients with melanoma treated with immune checkpoint inhibitors.

Cutaneous squamous cell carcinoma (cSCC) incidence and deaths continue to rise, underscoring the need for improved cSCC prevention. Elimination of actinic keratosis (AK) precursor lesions is a major strategy to prevent cSCC. Topical calcipotriol and 5-fluorouracil (5-FU) have been shown to eliminate AKs and reduce the risk of cSCC development, but the mechanism was undefined. In this issue of the JCI, Oka et al. demonstrate that type 2 immunity is necessary and sufficient for the elimination of premalignant keratinocytes and cSCC prevention. Paired biopsies from AK lesions and unaffected skin revealed that only keratinocytes from AKs produced thymic stromal lymphopoietin (TSLP) and damage-associated molecular patterns, resulting in selective recruitment of Th2 cells to the AK lesion. In mouse models of skin carcinogenesis, TSLP was necessary to recruit Th2 cells and trigger IL-24-mediated keratinocyte cell death. These findings suggest that the TSLP/Th2/IL-24 axis is a potential therapeutic target for SCC prevention.

Autoimmune diseases of the skin occur when the immune system attacks normal skin. The immune system can be broadly divided into an effector arm responsible for fighting infections and cancer and a regulatory arm that reduces autoreactivity and maintains immune homeostasis. Cutaneous autoimmunity develops when the equilibrium between the effector arm and regulatory arm of the immune system is disrupted. Recent insights into the inflammatory pathways that are overactive in some cutaneous autoimmune diseases have led to therapies targeting the effector arm of the immune system with greater treatment efficacy than previously used broad immunosuppressants. The current paradigm of inhibiting excessive immune activation for treating cutaneous autoimmunity will be discussed including cytokine blockade, cellular depletion, intracellular signaling blockade and costimulatory blockade. Despite the success of this approach many cutaneous autoimmune diseases lack a clearly delineated pathway to target and therefore new strategies are needed. An emerging therapeutic strategy targeting the regulatory arm of the immune system to induce tolerance and disease remission provides new hope for treating cutaneous autoimmunity. Such an approach includes cellular therapy with regulatory T cells and chimeric autoantibody receptor T cells, cytokine therapy with low-dose interleukin-2, immune checkpoint stimulation, tolerogenic vaccines and microbiome biotherapy. This mini-review will discuss the current and emerging therapeutic strategies for cutaneous autoimmune diseases and provide an organizational framework for understanding distinct mechanisms of action.

A carcinogen-induced mouse tumour model is used here to show that mutant tumour-specific antigens are targets for CD8 + T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy, and that these antigens can be used effectively in therapeutic vaccines; this advance potentially opens the door to personalized cancer vaccines. Targetting tumour-specific mutant antigens In many individuals, immunosuppression is mediated by T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), immunomodulatory receptors expressed on T cells. Matthew Gubin et al . use the MCA mouse sarcoma model to show that mutant tumour antigens serve as targets for CD8 + T-cell responses, mediating tumour regression after checkpoint blockade immunotherapy with anti-PD-1 and/or anti-CTLA-4. The authors demonstrate that these antigens can be used effectively in therapeutic vaccines, suggesting a possible route to personalized cancer vaccines. The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity 1 , 2 , 3 , 4 , 5 , 6 , but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion 1 , 2 , 7 . Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells 8 , 9 . Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits—including durable responses—to patients with different malignancies 10 , 11 , 12 , 13 . However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.