Melanoma-associated Vitiligo Research Articles

CD4 depletion enhances the efficacy of Super2 IL-33 armored CAR T cell against solid tumors and leads memory formation of both endogenous and CAR T cells

Abstract Chimeric antigen receptor (CAR) T cells exhibit tremendous efficacy in patients with relapsed and recurrent liquid cancers. However, CAR T cells fail to control solid tumors because of their inability to infiltrate the suppressive tumor environment and their poor persistence in vivo. The development of 4 thgeneration armored CAR T cells that employ direct tumor killing and release cytokines that can modulate the immune response to enhance tissue/tumor infiltration may improve CAR T cell persistence. Our lab has developed Super2 and IL-33 (S233) armored CAR T cells that significantly delayed B16F10 melanoma tumor growth and enhanced tumor infiltration of CARs and endogenous immune cells. Combination therapy of S233 CAR T Cells with anti-CTLA4 or anti-CD4 further enhanced this phenotype. S233 CAR T cells and anti-CD4 combination therapy promoted Melanoma-associated vitiligo (MAV), which correlates with development of tumor protective Tissue Resident Memory (TRM) cells. To assess whether CAR T cells differentiate into memory T cells, we treated tumor-bearing mice with S233 CAR T Cells with or without anti-CD4, resected their residual tumors and tracked memory T cell responses. We found that S233 CAR T cells persisted longer in the tumor draining lymph node and developed accelerated MAV when combined with anti-CD4. Both CAR T cells and endogenous T cells differentiated into central and effector memory but only endogenous T cells in the CD4 depleted group became TRM cells. While these findings provide insights on strategies to enhance long-term persistence of CAR T cells, additional studies are needed to induce CAR TRM cells and assess the durability of anti-tumor responses. NIH grant T32-AI007363 NIH grant P30-CA023108

Differences in the immune microenvironment between improved and non-improved cases of vitiligo after halo nevus excision

BackgroundHalo nevus, also called Sutton’s nevus, is a nevus cell nevus surrounded by vitiligo thought to be caused by a T-cell mediated immune response to the nevus antigen. The immune microenvironment is mysterious, however, as vitiligo often does not improve even when the nevus cells are removed. ObjectivesTo analyze the clinical course and immune microenvironment of patients with halo nevus who had undergone nevus excision. MethodsWe collected 54 halo nevus patients and performed multivariate analysis and immunohistochemical analysis, including multiplexed immune cell phenotyping and spatial single-cell analyses using the PhenoCycler® assay. ResultsMultivariate analysis revealed that only the presence or absence of vitiligo vulgaris at the time of consultation was associated with improvement in the surrounding vitiligo following excision. Expression of programmed death-ligand 1 in nevus cells was significantly higher in non-improved cases compared with improved cases. The PhenoCycler® assay revealed that CD107a-positive and CD21-positive cells were more prevalent in improved cases than in non-improved cases. In the improved cases, active cell-cell interactions, centered on CD21-positive cells, were observed, whereas in the non-improved cases, cell-cell interactions were sparse. Instead, a dense infiltration of CD8-positive cells and CD3 and CD4-positive cells was observed in non-improved cases. ConclusionElucidation of the immune microenvironment of halo nevus is also relevant to melanoma-associated vitiligo and will contribute to our understanding of tumor immunity.

Dendritic cells instruct differentiation of tissue resident memory T cells in the skin to promote durable tumor immunity

Abstract A subset of melanoma patients treated with immune checkpoint inhibitors develops vitiligo, a CD8 T cell-mediated autoimmune disease associated with improved patient survival. Using a melanoma-associated vitiligo (MAV) mouse model, CD8 tissue resident memory (TRM) T cells in vitiligo skin were found to be necessary and sufficient for durable tumor immunity. Using immunofluorescence microscopy, we found that skin TRM cells formed large aggregates with CD11c myeloid cells proximal to hair follicles. CD11c depletion resulted in TRM cell loss, revealing an unexpected requirement for continued T cell-dendritic cell (DC) interactions in TRM cell maintenance. We hypothesize that DCs provide instructive signals that are required for continued in situ maturation of CD8 TRM cells. To identify these signals, we disrupted Toll Like Receptor (TLR) signaling in DCs by ablating the MyD88 adapter protein and observed a reduction in skin TRM cell accumulation. This prompted us to explore a role for the microbiota in CD8 TRM formation. Treatment with broad spectrum antibiotics resulted in a 50% reduction in vitiligo incidence. B6 mice from vendors with microbiota differences, exhibited divergent MAV incidence, but upon cohousing or fecal transplantation, mice from both sources exhibited high MAV incidence. Collectively, these findings indicates that the gut-skin microbiota axis plays a critical role in generating tumor protective TRM cells. Future studies seek to identify microbial antigens responsible for promoting TRM differentiation. Supported by T32-AI007363 P30-CA023108

Vitiligo adverse events and associated medications as reported in the US Food and Drug Administration’s Adverse Event Reporting System from 2016 to 2021

Vitiligo adverse events and associated medications as reported in the US Food and Drug Administration’s Adverse Event Reporting System from 2016 to 2021

Progressive vitiligo induced by recurrent melanoma.

A woman had undergone excision for primary melanoma of the left heel and dissection of groin lymph nodes. The recurrent tumor on the lateral left lower leg developed six months ago and the depigmented plaques spread extensively on the left lower limb. The depigmented macules were localized to the left lower limb and were not seen in other areas. Although the left groin lymph node had been dissected, the local immune environment of anti‐tumor immunity was preserved. The cause of melanoma‐associated vitiligo is regarded to be anti‐tumor autoimmune mediated, and this phenomenon is recently recognized during the therapy with immune checkpoint inhibitors in the treatment of stage III and IV melanoma

033 Excision of halo nevus without PD-L1 expression may cure vitiligo

Halo nevus (HN), also called Sutton nevus, is a nevus cell nevus that is surrounded by vitiligo and is caused by a T-cell mediated immune response to the nevus antigen. Excision of nevus is recommended to prevent progression to vitiligo vulgaris. When vitiligo may occur around malignant melanoma, hemangioma, blue nevus, neurofibroma, senile wart, etc, it’s called Sutton’s phenomenon. Especially, vitiligo in melanoma patients is called “melanoma-associated vitiligo” and recognized to associate with favorable outcomes. It’s sometimes observed in patients who respond to immune checkpoint inhibitor (ICI) therapy as a “preferable” immune-related adverse event (irAE), the mechanism has attracted attention. However, there are few reports on analyses of immune checkpoint including PD-1/PD-L1 in HN. In the present study, to evaluate the relationship between immune checkpoint including PD-1/PD-L1 and HN, we performed immunohistochemical analysis using formalin-fixed paraffin-embedded (FFPE) samples collected from 38 HN patients (16 males and 22 females, mean age 20.47 years) whose nevus were resected in Nagoya City University Hospital. Of the 29 cases that we were able to follow after nevus excision, 12 cases showed improvement of the surrounding vitiligo and 17 cases showed no change or expansion of vitiligo. 25 cases have vitiligo vulgaris, and 10 of them showed improvement of vitiligo vulgaris after HN excision. Immunohistochemical findings showed that PD-L1 expression was positive in 25 of 36 cases, and cases with improved vitiligo after nevus excision were predominantly PD-L1 negative. PD-1 expression in infiltrating cells was positive in 19 of 38 patients, but there was no significant correlation between PD-1 expression and improvement of vitiligo. These results suggest that more than local immune responses are involved in vitiligo formation in PD-L1-positive HN, and the analysis of immune responses in PD-L1-positive HN may lead to elucidation of the mechanisms of tumor immunity and irAEs

Resident memory CD8+ T cells in regional lymph nodes mediate immunity to metastatic melanoma

The nature of the anti-tumor immune response changes as primary tumors progress and metastasize. We investigated the role of resident memory (Trm) and circulating memory (Tcirm) cells in anti-tumor responses at metastatic locations using a mouse model of melanoma-associated vitiligo. We found that the transcriptional characteristics of tumor-specific CD8+ Tcells were defined by the tissue of occupancy. Parabiosis revealed that tumor-specific Trm and Tcirm compartments persisted throughout visceral organs, but Trm cells dominated lymph nodes (LNs). Single-cell RNA-sequencing profiles of Trm cells in LN and skin were distinct, and T cell clonotypes that occupied both tissues were overwhelmingly maintained as Trm in LNs. Whereas Tcirm cells prevented melanoma growth in the lungs, Trm afforded long-lived protection against melanoma seeding in LNs. Expanded Trm populations were also present in melanoma-involved LNs from patients, and their transcriptional signature predicted better survival. Thus, tumor-specific Trm cells persist in LNs, restricting metastatic cancer.

Vitiligo and Melanoma-Associated Vitiligo: Understanding Their Similarities and Differences.

There has been a significant increase in the number and efficacy of therapies for advanced melanoma. Immunotherapies, such as anti-cytotoxic T-lymphocyte antigen-4 and programmed cell death-1 inhibitors, have improved the prognosis for patients with advanced melanoma. While spontaneous melanoma-associated vitiligo is a known phenomenon, the occurrence of melanoma-associated vitiligo following melanoma therapy is now recognized to associate with favorable outcomes. The objective of this article is to provide a comprehensive literature review of melanoma-associated vitiligo and explore the insights these findings provide about the pathobiology of vitiligo and mechanisms underlying melanoma therapies. PubMed and Science Direct databases were searched for studies pertaining to melanoma-associated vitiligo. The 36 studies reviewed included meta-analyses (n = 2), prospective cohort studies (n = 4), prospective observational studies (n = 3), retrospective studies (n = 12), case series (n = 2), and case reports (n = 13). The basic mechanisms underlying melanoma-associated vitiligo and vitiligo may be shared. Characterization of these mechanisms will identify new biomarkers and therapeutic targets for both melanoma and vitiligo. Co-opting the immune system to target tumor antigens highlights the potential overlap between anti-tumor immunity and autoimmunity. The development of vitiligo-like depigmentation in association with immunotherapy for melanoma may provide insights into both the immune response against melanoma as well as the pathogenesis of vitiligo.

Lymphocyte aggregates accumulate in the skin of melanoma associated autoimmune vitiligo

Abstract While melanoma is not the most common form of skin cancer, it is responsible for the majority of skin cancer related deaths. A small percentage of people that develop melanoma simultaneously develop autoimmune vitiligo, resulting in a favorable prognosis for these individuals. Melanoma associated vitiligo is a CD8+ T cell mediated disease that results in the death of healthy melanocytes. The destruction of melanocytes generates the self antigen(s) required for memory CD8 T cells that persist long term and provide protection from melanoma. Although the link between autoimmune vitiligo and anti-melanoma immunity has long been established and well studied, the mechanisms driving vitiligo and tumor protection still remain unknown. Using a mouse model of melanoma-associated vitiligo we are investigating this intimate relationship. Using multiparameter immunohistochemistry, we have identified large aggregates of lymphocytes clustered throughout the initial site of depigmentation. These lymphoid aggregates are comprised of a number of different lymphocyte subsets including CD4 and CD8 T cells, dendritic cells and macrophages. However, they are distinct in composition, duration and location from tertiary lymphoid organs and other lymphocyte clusters identified in the setting of HSV infection. Only vitiligo-affected mice develop these aggregates suggesting they may be important in the vitiligo development or dissemination and/or tumor protection. Understanding the role these lymphocyte aggregates play in vitiligo will give us a better understanding on the mechanisms required for both autoimmune vitiligo and anti-melanoma immunity.

Vitiligo‐like depigmentations as the first sign of melanoma: a retrospective case series from a tertiary vitiligo centre

patients with melanoma may develop vitiligo-like skin depigmentation referred to as melanoma-associated leukoderma (MAL), melanoma-associated hypopigmentation (MAH), melanoma-associated depigmentation (MAD) or melanoma-associated vitiligo (MAV) 1-3. Many dermatologists are not aware of the diagnosis MAL and may easily diagnose and treat these patients as having non-segmental vitiligo, thereby overlooking the underlying (metastatic) melanoma. At present, the prevalence of MAL and its clinical characteristics are not well established. This article is protected by copyright. All rights reserved.

Melanoma-associated leukoderma and vitiligo cannot be differentiated based on blinded assessment by experts in the field

Melanoma-associated leukoderma (MAL) is a depigmenting disorder that can occur spontaneously in patients with melanoma. The differences in clinical presentation between MAL and vitiligo are not well defined. This may lead to misdiagnosing MAL as vitiligo, resulting in delayed detection of melanoma. The objective of this study was to assess whether experts in the field can distinguish between MAL and vitiligo, and to assess if discriminative features can be identified. We designed an image comparison study in which 4 experts in the field blindly assessed photographs followed by medical history of 11 patients with MAL and 33 with vitiligo. The assessors misdiagnosed 72.7% of MAL cases and marked 80.0% of them as typical vitiligo. The median age at onset of the leukoderma was higher (55years, P=.001) in MAL. No discriminative features were found. Sampling bias because of inclusion in tertiary referral center is a limitation. The clinical presentation of leukoderma in patients with melanoma resembles that of vitiligo. We propose "melanoma-associated vitiligo" as the more appropriate term for leukoderma in patients withmelanoma. Clinicians should be aware that depigmentation in vitiligo can also be caused by melanoma-associated vitiligo and a total body inspection should be performed.

Melanoma‐associated leukoderma – immunology in black and white?

Melanoma is an 'immunogenic tumor', often highly infiltrated with lymphocytes, which are capable of inducing regression of the primary tumor. The commonly observed phenomenon of regression suggests substantial cross-talk between immune cells and transformed melanocytes. An immune response to melanocyte differentiation antigens common to transformed and normal melanocytes manifests clinically at distant sites as melanoma-associated vitiligo or halo nevi. Despite similar antigenic targets, the pathogenesis and prognosis differ between the different melanoma-associated leukodermas. Understanding immunologic cross-talk between melanocytes and the immune system will aid the development of approaches to combat melanoma.

New perspectives on the role of vitiligo in immune responses to melanoma.

Melanoma-associated vitiligo is the best-studied example of the linkage between tumor immunity and autoimmunity. Although vitiligo is an independent positive prognostic factor for melanoma patients, the autoimmune destruction of melanocytes was long thought to be merely a side effect of robust anti-tumor immunity. However, new data reveal a key role for vitiligo in supporting T cell responses to melanoma. This research perspective reviews the history of melanoma-associated vitiligo in patients, the experimental studies that form the basis for understanding this relationship, and the unique characteristics of melanoma-specific CD8 T cells found in hosts with vitiligo. We also discuss the implications of our recent findings for the interpretation of patient responses, and the design of next-generation cancer immunotherapies.

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study

BackgroundThe clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma. Materials and methodsA total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate. ResultsVitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P=0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV. ConclusionMelanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.

The course of melanoma-associated vitiligo: report of a case

The appearance of vitiligo-like lesions in patients with malignant melanoma is a well-known yet uncommon phenomenon. This finding is especially reported in patients undergoing immunotherapy with or without chemotherapy for malignant melanoma and is generally believed to be associated with a better prognosis. We report a case of preexisting vitiligo in a 48-year-old man, aggravated after chemo-immunotherapy of pulmonary metastatic melanoma with interferon-alpha, vinblastine and dacarbazine. Skin lesions remained stable after discontinuation of the treatment, and repigmentation heralded the recurrence of metastatic disease. These findings were in favor of vitiligo being a marker of the immunity against melanoma cells and its favorable impact on the prognosis of melanoma patients.

Spontaneous vitiligo in an animal model for human melanoma: role of tumor-specific CD8+ T cells.

Tumor antigen-reactive T cells can be detected in a large proportion of melanoma patients, but their efficacy on tumor control in vivo remains unclear. On the other hand, vitiligo, a skin disorder characterized by patchy depigmented macules, may occur spontaneously or after antitumor therapies. Moreover, vitiligo is significantly associated with positive clinical response, but the mechanism is not understood. Therefore, the establishment of a relevant animal model in which melanoma and vitiligo spontaneously develop stepwise may be useful for better understanding of the parameters involved in the destruction of both benign and malignant melanocytes. In a previous work, we established a mouse model for melanoma in which MT/ret transgenic mice express the ret oncogene fused to the metallothionein promoter. Here we report that melanoma leads to spontaneous vitiligo. We further investigate, for the first time in this model, the natural antitumor T-cell response and evaluate the role of cellular immunity in the development of the disease. Interestingly, the occurrence of spontaneous tumor nodules in MT/ret mice with melanoma-associated vitiligo is significantly delayed when compared in melanoma mice without vitiligo. Moreover, a significant proportion of mice with melanoma-associated vitiligo resisted a challenge with syngeneic melanoma cells in contrast to animals without vitiligo. Our results confirm that vitiligo is associated with clinical benefit and further demonstrate the crucial role of CD8+ T cells for tumor control in melanoma-associated vitiligo.

Direct Evidence to Support the Role of Antigen-Specific CD8+ T Cells in Melanoma-Associated Vitiligo

Vitiligo is a cutaneous pigmentary disorder characterized by the loss of melanocytes. An autoimmune mechanism is strongly suspected to be involved in this affection given that it is frequently associated with autoimmune hormonal disorders, and because antibodies directed against melanocytic antigens are found in the serum of patients with vitiligo. We examined the role of cellular immunity in melanoma-associated vitiligo by expanding infiltrating lymphocytes from fresh biopsy specimens of vitiligo patches in melanoma patients. The vitiligo-infiltrating lymphocytes were almost exclusively T lymphocytes, and most were CD8(+). Following in vitro expansion, vitiligo-infiltrating lymphocytes remained predominantly CD8(+) and expressed the cutaneous homing receptor CLA. Furthermore, vitiligo-infiltrating lymphocytes had a clonal or oligoclonal T cell receptor profile, possibly reflecting specific antigenic stimulation. Finally, vitiligo- infiltrating lymphocytes specifically recognized differentiation antigens shared by normal melanocytes and melanoma cells. This direct demonstration of CD8(+) T cell involvement in vitiligo suggests that, in melanoma patients, vitiligo may be a visible effect of a spontaneous antitumoral immune response.