RESUMO
Senescent cell accumulation has been implicated in the pathogenesis of aging-associated diseases, including cancer. The mechanism that prevents the accumulation of senescent cells in aging human organs is unclear. Here, we demonstrate that a virus-immune axis controls the senescent fibroblast accumulation in the human skin. Senescent fibroblasts increased in old skin compared with young skin. However, they did not increase with advancing age in the elderly. Increased CXCL9 and cytotoxic CD4+ T cells (CD4 CTLs) recruitment were significantly associated with reduced senescent fibroblasts in the old skin. Senescent fibroblasts expressed human leukocyte antigen class II (HLA-II) and human cytomegalovirus glycoprotein B (HCMV-gB), becoming direct CD4 CTL targets. Skin-resident CD4 CTLs eliminated HCMV-gB+ senescent fibroblasts in an HLA-II-dependent manner, and HCMV-gB activated CD4 CTLs from the human skin. Collectively, our findings demonstrate HCMV reactivation in senescent cells, which CD4 CTLs can directly eliminate through the recognition of the HCMV-gB antigen.
Assuntos
Antineoplásicos , Infecções por Citomegalovirus , Humanos , Idoso , Citomegalovirus , Linfócitos T Citotóxicos , Antígenos HLA , Linfócitos T CD4-Positivos , Senescência CelularRESUMO
Giant congenital melanocytic nevi are NRAS-driven proliferations that may cover up to 80% of the body surface. Their most dangerous consequence is progression to melanoma. This risk often triggers preemptive extensive surgical excisions in childhood, producing severe lifelong challenges. We have presented preclinical models, including multiple genetically engineered mice and xenografted human lesions, which enabled testing locally applied pharmacologic agents to avoid surgery. The murine models permitted the identification of proliferative versus senescent nevus phases and treatments targeting both. These nevi recapitulated the histologic and molecular features of human giant congenital nevi, including the risk of melanoma transformation. Cutaneously delivered MEK, PI3K, and c-KIT inhibitors or proinflammatory squaric acid dibutylester (SADBE) achieved major regressions. SADBE triggered innate immunity that ablated detectable nevocytes, fully prevented melanoma, and regressed human giant nevus xenografts. These findings reveal nevus mechanistic vulnerabilities and suggest opportunities for topical interventions that may alter the therapeutic options for children with congenital giant nevi.
Assuntos
Melanoma , Nevo Pigmentado , Neoplasias Cutâneas , Animais , Xenoenxertos , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Camundongos , Transplante de Neoplasias , Nevo Pigmentado/congênito , Nevo Pigmentado/tratamento farmacológico , Nevo Pigmentado/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/prevenção & controleRESUMO
Skin cancer is the leading malignancy in immunosuppressed patients, including organ transplant recipients (OTRs), which is increasing in incidence as OTRs live longer. We performed a single-center case series of 4 patients with scalp pleomorphic dermal sarcoma and a history of multiple keratinocyte carcinomas. Outcomes included incidence of dermal sarcoma, dermal sarcoma-related mortality, and histopathologic findings. Out of more than 200 patients followed over a 3-year period in Massachusetts General Hospital High Risk Skin Cancer Clinics, all skin cancer-related deaths (2/2) were due to metastatic dermal sarcoma. Three of 4 patients diagnosed with scalp dermal sarcoma were OTRs and had been on at least one immunosuppressive medication for a median of 9 years. For patients who died from dermal sarcoma, the median time between diagnosis and death was 6 months. Our findings suggest pleomorphic dermal sarcoma contributes to skin cancer-related morbidity and mortality in OTRs.
Assuntos
Transplante de Órgãos , Sarcoma , Neoplasias Cutâneas , Humanos , Hospedeiro Imunocomprometido , Transplante de Órgãos/efeitos adversos , Sarcoma/complicações , Neoplasias Cutâneas/patologia , TransplantadosRESUMO
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Fator Regulador 3 de Interferon , Interleucina-33 , Neoplasias Pancreáticas , Proteínas Serina-Treonina Quinases , Quinolinas , Transdução de Sinais , Animais , Feminino , Humanos , Masculino , Camundongos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/prevenção & controle , Inflamação/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Interleucina-33/efeitos dos fármacos , Interleucina-33/metabolismo , Ácido Mevalônico/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Pancreáticas/prevenção & controle , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Pancreatite Crônica/prevenção & controle , Pancreatite Crônica/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Receptor 3 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismoRESUMO
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.
RESUMO
Thymic stromal lymphopoietin (TSLP) overexpression is widely associated with atopy. However, TSLP is expressed in normal barrier organs, suggesting a homeostatic function. To determine the function of TSLP in barrier sites, we investigated the impact of endogenous TSLP signaling on the homeostatic expansion of CD4+ T cells in adult mice. Surprisingly, incoming CD4+ T cells induced lethal colitis in adult Rag1-knockout animals that lacked the TSLP receptor (Rag1KOTslprKO). Endogenous TSLP signaling was required for reduced CD4+ T cell proliferation, Treg differentiation, and homeostatic cytokine production. CD4+ T cell expansion in Rag1KOTslprKO mice was dependent on the gut microbiome. The lethal colitis was rescued by parabiosis between Rag1KOTslprKO and Rag1KO animals and wild-type dendritic cells (DCs) suppressed CD4+ T cell-induced colitis in Rag1KOTslprKO mice. A compromised T cell tolerance was noted in TslprKO adult colon, which was exacerbated by anti-PD-1 and anti-CTLA-4 therapy. These results reveal a critical peripheral tolerance axis between TSLP and DCs in the colon that blocks CD4+ T cell activation against the commensal gut microbiome.
Assuntos
Colite , Microbioma Gastrointestinal , Linfopoietina do Estroma do Timo , Animais , Camundongos , Linfócitos T CD4-Positivos , Diferenciação Celular , Citocinas/metabolismo , Células Dendríticas , Linfócitos T Reguladores , Linfopoietina do Estroma do Timo/metabolismoRESUMO
Carcinogen exposure is strongly associated with enhanced cancer immunogenicity. Increased tumor mutational burden and resulting neoantigen generation have been proposed to link carcinogen exposure and cancer immunogenicity. However, the neoantigen-independent immunological impact of carcinogen exposure on cancer is unknown. Here, we demonstrate that chemical carcinogen-exposed cancer cells fail to establish an immunosuppressive tumor microenvironment (TME), resulting in their T cell-mediated rejection in vivo. A chemical carcinogen-treated breast cancer cell clone that lacked any additional coding region mutations (i.e., neoantigen) was rejected in mice in a T cell-dependent manner. Strikingly, the coinjection of carcinogen- and control-treated cancer cells prevented this rejection, suggesting that the loss of immunosuppressive TME was the dominant cause of rejection. Reduced M-CSF expression by carcinogen-treated cancer cells significantly suppressed tumor-associated macrophages (TAMs) and resulted in the loss of an immunosuppressive TME. Single-cell analysis of human lung cancers revealed a significant reduction in the immunosuppressive TAMs in former smokers compared with individuals who had never smoked. These findings demonstrate that carcinogen exposure impairs the development of an immunosuppressive TME and indicate a novel link between carcinogens and cancer immunogenicity.
Assuntos
Carcinógenos , Neoplasias Pulmonares , Humanos , Animais , Camundongos , Carcinógenos/toxicidade , Microambiente Tumoral , Linfócitos T , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Biomarcadores Tumorais/metabolismo , Imunoterapia/métodosRESUMO
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by the environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas. FDA-approved drug library screen identified pitavastatin as an effective IL-33 inhibitor by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevented chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. IRF3-IL-33 axis was highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlated with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3 signaling pathway suppresses IL-33 expression and cancer-prone chronic inflammation. Statins present a safe and effective therapeutic strategy to prevent chronic inflammation and its cancer sequela.
RESUMO
STK11 is implicated as a tumor suppressor in epithelial cancer invasion and metastasis. In their new article in the Journal of Investigative Dermatology, Dzung et al. (2021) show that loss of STK11 in cutaneous melanoma cells leads to an invasive metastatic phenotype through the activation of the signal transducer and activator of transcription (STAT) 3/5 and FAK signaling pathways. These results suggest that inhibition of STAT3/5 and FAK in STK11-deficient melanoma cells could serve as a novel therapeutic strategy against metastatic melanoma.
Assuntos
Melanoma , Neoplasias Cutâneas , Quinases Proteína-Quinases Ativadas por AMP , Linhagem Celular Tumoral , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/metabolismo , Metástase Neoplásica , Proteínas Serina-Treonina Quinases/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismoRESUMO
Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer, with its incidence rising steeply. Immunosuppression is a well-established risk factor for cSCC, and this risk factor highlights the critical role of the immune system in regulating cSCC development and progression. Further highlighting the nature of cSCC as an immunological disorder, substantial evidence demonstrates a tight association between cSCC risk and age-related immunosenescence. Besides the proven efficacy of immune checkpoint blockade therapy for advanced cSCC, novel immunotherapy that targets cSCC precursor lesions has shown efficacy for cSCC prevention. Furthermore, the appreciation of the interplay between keratinocytes, commensal papillomaviruses, and the immune system has revealed the possibility for the development of a preventive cSCC vaccine. cSCC shares fundamental aspects of its origin and pathogenesis with mucosal SCCs. Therefore, advances in the field of cSCC immunoprevention will inform our approach to the management of mucosal SCCs and potentially other epithelial cancers.
Assuntos
Vacinas Anticâncer , Carcinoma de Células Escamosas , Neoplasias Cutâneas , Vacinas Anticâncer/uso terapêutico , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/prevenção & controle , Humanos , Imunoterapia , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/prevenção & controleRESUMO
Thymic Stromal Lymphopoietin (TSLP) plays a prominent role in inducing type 2 immune response, commonly associated with atopic diseases. TSLP-activated CD4+ T helper 2 cells block early carcinogenesis by inducing terminal differentiation in spontaneous breast and lung cancer models. However, the impact of TSLP induction on advanced cancer with altered cellular phenotypes is unclear. Using an established MMTV-PyMttg breast cancer cell line, we demonstrate that TSLP-stimulated CD4+ T cells possess an antitumor effect in advanced breast cancer. In contrast to early breast cancer suppression, the antitumor immunity mediated by TSLP-stimulated CD4+ T cells in advanced breast cancer is mediated by the induction of a senescent-like phenotype in cancer cells. Inflammatory CD4+ T cells drive breast cancer cells into senescence by releasing interferon-gamma and tumor necrosis factor-alpha, which directly bind to their receptors on cancer cells. Our findings reveal a novel mechanism of TSLP-activated CD4+ T cell immunity against advanced breast cancer, mediated by cellular senescence as a distinct effector mechanism for cancer immunotherapy.
RESUMO
Despite significant advances in cancer treatment, the metastatic spread of malignant cells to distant organs remains a major cause of cancer-related deaths. Natural killer (NK) cells play a crucial role in controlling tumor metastasis; however, the dynamics of NK cell-mediated clearance of metastatic tumors are not entirely understood. Herein, we demonstrate the cooperative role of NK and T cells in the surveillance of melanoma metastasis. We found that NK cells effectively limited the pulmonary seeding of B16 melanoma cells, while T cells played a primary role in restricting metastatic foci growth in the lungs. Although the metastatic foci in the lungs at the endpoint were largely devoid of NK cells, they played a prominent role in promoting T cell recruitment into the metastatic foci. Our data suggested that the most productive interaction between NK cells and metastatic cancer cells occurred when cancer cells were in circulation. Modifying the route of administration so that intravenously injected melanoma cells bypass the first liver passage resulted in significantly more melanoma metastasis to the lung. This finding indicated the liver as a prominent site where NK cells cleared melanoma cells to regulate their seeding in the lungs. Consistent with this notion, the liver and the lungs of the tumor-bearing mice showed dominance of NK and T cell activation, respectively. Thus, NK cells and T cells control pulmonary metastasis of melanoma cells by distinct mechanisms where NK cells play a critical function in shaping T cell-mediated in situ control of lung-seeded cancer cells. A precise understanding of the cooperative role of NK and T cells in controlling tumor metastasis will enable the development of the next generation of cancer immunotherapies.
Assuntos
Neoplasias Pulmonares , Melanoma Experimental , Células Neoplásicas Circulantes , Camundongos , Animais , Células Matadoras Naturais/patologia , Melanoma Experimental/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologiaRESUMO
Lung cancer is the leading cause of cancer deaths in the United States and across the world. Immunotherapies, which activate tumor-infiltrating cytotoxic T lymphocytes, have demonstrated efficacy for the treatment of advanced-stage lung cancer. However, the potential for harnessing the immune system against the early stages of lung carcinogenesis to prevent cancer development and recurrence remains unexplored. Using a mouse model of lung adenocarcinoma, we investigated the effects of thymic stromal lymphopoietin (TSLP) induction on early cancer development in the lungs. Herein, we demonstrate that systemic TSLP induction suppressed spontaneous lung cancer development in KrasG12D mice. TSLP drove a significant CD4+ T cell response to block lung cancer progression from atypical alveolar hyperplasia to adenocarcinoma. Our findings suggest that TSLP can be used in the early stages of lung cancer development to trigger a lasting immunity in the tissue and prevent the development of advanced disease.
RESUMO
The importance of innate immune cells in cancer promotion has been long recognized. Luci et al. (2021) show a key role for innate lymphoid cells (ILCs) in controlling precancerous skin lesions and impaired function of NK cells and ILC1s during progression to cutaneous squamous cell carcinoma (cSCC). These results, together with other findings, suggest that activation of ILCs could serve as a novel immunotherapeutic strategy against cSCC.