The skin provides the first line of physical and immunological defense against environmental insults. However, the age-related changes in the immune function of human skin are unclear. Here, we ...investigated the age-related changes in epidermal Langerhans cells (LCs), which play a sentinel role in the initiation of the immune responses in the skin. We found a significant reduction in the number of epidermal LCs in sun-protected skin with age. Among the possible explanations for this reduction, the number of CD14+ CD207+ CCR6+ dermal-resident monocytes that can differentiate into epidermal LCs was markedly reduced with age (P = 0.0057). Among the chemokines that can recruit these cells into the skin, the expression of CXCL14 was significantly down-regulated in epidermal keratinocytes with age. In addition, we discovered that young skin recruited a significantly higher number of monocytic THP-1 cells compared with old skin ex vivo. This recruitment was blocked by CXCL14 neutralizing antibody and conversely promoted by CXCL14 treatment. Collectively, our findings indicate that decreased CXCL14-mediated recruitment of CD14+ monocytes in human skin results in the reduction of epidermal LCs with age, and CXCL14 may provide a therapeutic target for the prevention of age-related reduction in LCs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Immunosuppression increases the risk of cancers that are associated with viral infection
. In particular, the risk of squamous cell carcinoma of the skin-which has been associated with beta human ...papillomavirus (β-HPV) infection-is increased by more than 100-fold in immunosuppressed patients
. Previous studies have not established a causative role for HPVs in driving the development of skin cancer. Here we show that T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts, and the loss of this immunity-rather than the oncogenic effect of HPVs-causes the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the effects of papillomavirus on carcinogen-driven skin cancer, we colonized several strains of immunocompetent mice with mouse papillomavirus type 1 (MmuPV1)
. Mice with natural immunity against MmuPV1 after colonization and acquired immunity through the transfer of T cells from immune mice or by MmuPV1 vaccination were protected against skin carcinogenesis induced by chemicals or by ultraviolet radiation in a manner dependent on CD8
T cells. RNA and DNA in situ hybridization probes for 25 commensal β-HPVs revealed a significant reduction in viral activity and load in human skin cancer compared with the adjacent healthy skin, suggesting a strong immune selection against virus-positive malignant cells. Consistently, E7 peptides from β-HPVs activated CD8
T cells from unaffected human skin. Our findings reveal a beneficial role for commensal viruses and establish a foundation for immune-based approaches that could block the development of skin cancer by boosting immunity against the commensal HPVs present in all of our skin.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Chronic inflammation’s tumor-promoting potential is well-recognized; however, the mechanism underlying the development of this immune environment is unknown. Studying the transition from acute, ...tumor-suppressive to chronic, tumor-promoting allergic contact dermatitis (ACD) revealed how tumor-promoting chronic inflammation develops. Epidermis-derived interleukin (IL)-33 up-regulation and its induction of regulatory T cell (Treg) accumulation in the skin preceded the transition from acute to chronic ACD and triggered the tumor-promoting immune environment in chronic ACD. Mice lacking IL-33 were protected from chronic ACD and its skin cancer sequela compared with wild-type controls (P = 0.0002). IL-33’s direct signaling onto Tregs was required for the development of the tumor-promoting immune environment in the skin. IL-33–Treg signaling was also required for chronic colitis and its associated colorectal cancer development in a colitis model (P < 0.0001). Significantly increased IL-33 and Tregs marked the perilesional skin and colon in patients with cancer-prone chronic inflammatory diseases. Our findings elucidate the role of the IL-33/Treg axis in creating a tumor-promoting immune environment in chronic inflammatory diseases and suggest therapeutic targets for cancer prevention and treatment in high-risk patients.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Advances in the field of cancer immunology, including studies on tumor-infiltrating CD8+ cytotoxic T lymphocytes (CTLs), have led to new immunotherapeutics with proven efficacy against late-stage ...cancers. However, the antitumor potential of the immune system in targeting early-stage cancers remains uncertain. Here, we demonstrated that both genetic and chemical induction of thymic stromal lymphopoietin (TSLP) at a distant site leads to robust antitumor immunity against spontaneous breast carcinogenesis in mice. Breast tumors exposed to high circulating levels of TSLP were arrested at an early adenoma-like stage and were prevented from advancing to late carcinoma and metastasis. Additionally, CD4+ Th2 cells mediated the antitumor effects of TSLP, challenging the notion that Th2 cells only promote cancer. We also discovered that TSLP is expressed by the breast tumor cells themselves and acts to block breast cancer promotion. Moreover, TSLP-induced immunity also blocked early stages of pancreatic cancer development. Together, our findings demonstrate that TSLP potently induces immunity directed against early stages of breast cancer development without causing inflammation in the normal breast tissue. Moreover, our results highlight a previously unappreciated function of the immune system in controlling the early development of cancer and establish a fundamental role for TSLP and Th2 cells in tumor immunity against early-stage cancers.
The zinc-finger transcription factor Helios is critical for maintaining the identity, anergic phenotype and suppressive activity of regulatory T (T
) cells. While it is an attractive target to ...enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of T
cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small-molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
High-risk skin cancer is a rare, but severe, complication associated with discoid lupus erythematosus (DLE). Chronic scar, inflammation, UVR, and immunosuppressive medications are proposed ...explanations for this heightened skin cancer risk; however, the exact mechanism driving skin carcinogenesis in DLE is unknown. The distinct co-localization of multiple independent skin cancers with areas of active inflammation in two DLE patients followed over 8 years strongly suggested that lupus inflammation promotes skin carcinogenesis in DLE. To investigate this clinical observation, we subjected lupus-prone MRL/lpr and control (MRL/n) mice to a skin carcinogenesis protocol. Skin tumors developed preferentially within the cutaneous lupus inflammation without scarring in MRL/lpr mice (P < 0.01). The inflammation in MRL/lpr skin was characterized by the accumulation of regulatory T cells, mast cells, M2 macrophages, and markedly elevated transforming growth factor-β1 and IL-6 levels, which have been linked to tumor promotion. Tacrolimus treatment reduced skin inflammation and blocked cancer development in MRL/lpr mice (P = 0.0195). A similar tumor-promoting immune environment was detected in SCCs and the perilesional skin of cancer-prone DLE patients. Therefore, discoid lupus inflammation promotes skin cancer in high-risk DLE patients, and blocking the inflammation may be critical for preventing this life-threatening complication of DLE.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Topical calcipotriol plus 5-fluorouracil (5-FU) combination is an effective immunotherapy against actinic keratosis (AK), which is a precursor to squamous cell carcinoma (SCC). However, the long-term ...effectiveness of calcipotriol plus 5-FU treatment for SCC prevention is unknown.
We performed a blinded prospective cohort study on participants of a randomized double-blind clinical trial in which a 4-day course of topical calcipotriol plus 5-FU combination was compared to Vaseline plus 5-FU (control) for AK treatment. SCC and basal cell carcinoma (BCC) incidences were assessed at 1, 2, and 3 years after trial. Tissues were analyzed for calcipotriol plus 5-FU-induced T cell immunity in the skin.
Calcipotriol plus 5-FU-induced tissue-resident memory T (Trm) cell formation in face and scalp skin associated with significantly higher erythema scores compared with control (P < 0.01). Importantly, more participants in the test cohort remained SCC-free over the more than 1,500-day follow-up period (P = 0.0765), and significantly fewer developed SCC on the treated face and scalp within 3 years (2 of 30 7% versus 11 of 40 28% in control group, hazard ratio 0.215 95% CI: 0.048-0.972, P = 0.032). Accordingly, significantly more epidermal Trm cells persisted in the calcipotriol plus 5-FU-treated face and scalp skin compared with control (P = 0.0028). There was no significant difference in BCC incidence between the treatment groups.
A short course of calcipotriol plus 5-FU treatment on the face and scalp is associated with induction of robust T cell immunity and Trm formation against AKs and significantly lowers the risk of SCC development within 3 years of treatment.
This research was supported by internal academic funds and by grants from the Burroughs Wellcome Fund, Sidney Kimmel Foundation, Cancer Research Institute, and NIH.
Nonkeratinocyte cutaneous malignancies, including breast cancer cutaneous metastasis and melanoma in situ, are often poor surgical candidates. Imiquimod (IMQ), a toll-like receptor 7 agonist that ...activates innate immunity in the skin, is used to treat these cutaneous malignancies. However, IMQ's modest effect on the activation of adaptive immunity limits its efficacy as a monotherapy. In this study, we demonstrate that topical TSLP cytokine inducers—calcipotriol and retinoic acid—synergize with IMQ to activate CD4+ T-cell immunity against nonkeratinocyte cutaneous malignancies. Topical calcipotriol plus IMQ treatment reduced breast tumor growth compared with calcipotriol or IMQ alone (P < 0.0001). Calcipotriol plus IMQ–mediated tumor suppression was associated with significant infiltration of CD4+ effector T cells in the tumor microenvironment. Notably, topical calcipotriol plus IMQ immunotherapy enabled immune checkpoint blockade therapy to effectively control immunologically cold breast tumors, which was associated with induction of CD4+ T-cell immunity. Topical treatment with calcipotriol plus IMQ and retinoic acid plus IMQ also blocked subcutaneous melanoma growth. These findings highlight the synergistic effect of topical TSLP induction in combination with innate immune cell activation as an effective immunotherapy for malignancies affecting the skin.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for
-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired ...drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in
-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.
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Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to cotarget RAS and mTOR pathways; however, ...toxicity due to broad mTOR inhibition has limited its utility. Therefore, we sought to develop a more refined means of targeting cap-dependent translation and identifying the most therapeutically important eukaryotic initiation factor 4F complex-translated (eIF4F-translated) targets. Here, we show that an eIF4A inhibitor, which targets a component of eIF4F, dramatically enhances the effects of KRAS G12C inhibitors in NSCLCs and together these agents induce potent tumor regression in vivo. By screening a broad panel of eIF4F targets, we show that this cooperativity is driven by effects on BCL-2 family proteins. Moreover, because multiple BCL-2 family members are concomitantly suppressed, these agents are broadly efficacious in NSCLCs, irrespective of their dependency on MCL1, BCL-xL, or BCL-2, which is known to be heterogeneous. Finally, we show that MYC overexpression confers sensitivity to this combination because it creates a dependency on eIF4A for BCL-2 family protein expression. Together, these studies identify a promising therapeutic strategy for KRAS-mutant NSCLCs, demonstrate that BCL-2 proteins are the key mediators of the therapeutic response in this tumor type, and uncover a predictive biomarker of sensitivity.
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