Epidermal DNA damage, especially to the basal layer, is an established cause of keratinocyte cancers (KCs). Large differences in KC incidence (20‐ to 60‐fold) between white and black populations are ...largely attrib utable to epidermal melanin photoprotection in the latter. The cyclobutane pyrimidine dimer (CPD) is the most mutagenic DNA photolesion; however, most studies suggest that melanin photoprotection against CPD is modest and cannot explain the considerable skin color‐based differences in KC incidence. Along with melanin quantity, solar‐simulated radiation‐induced CPD assessed immediately postexposure in the overall epidermis and within 3 epidermal zones was compared in black West Africans and fair Europeans. Melanin in black skin protected against CPD by 8.0‐fold in the overall epidermis and by 59.0‐, 16.5‐, and 5.0‐fold in the basal, middle, and upper epidermis, respectively. Protection was related to the distribution of melanin, which was most concentrated in the basal layer of black skin. These results may explain, at least in part, the considerable skin color differences in KC incidence. These data suggest that a DNA protection factor of at least 60 is necessary in sunscreens to reduce white skin KC incidence to a level that is comparable with that of black skin.—Fajuyigbe, D., Lwin, S. M., Diffey, B. L., Baker, R., Tobin, D. J., Sarkany, R. P. E., Young, A. R. Melanin distribution in human epidermis affords localized protection against DNA photodamage and concurs with skin cancer incidence difference in extreme phototypes. FASEB J. 32, 3700–3706 (2018). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Despite seasonal variation in malignant melanoma diagnosis being well described, data on the annual variation in high-risk melanomas are scarce.
We set out to investigate the relationship between ...seasonality, the incidence of melanoma, and the distribution of melanoma characteristics, including Breslow thickness, ulceration, mitotic rate, lymphovascular and perineural invasion, and the presence of microsatellites.
Primary cutaneous malignant melanomas diagnosed between 2011 and 2019 in Eastern England were identified from our prospectively maintained melanoma database (n = 2199). These were analysed by year and season of diagnosis, patient demographics, and melanoma characteristics.
There was a variation in rates of melanoma diagnosis across the year, with Summer having the highest incidence (p < 0.0001). There was a significant trend towards more male than female diagnosis in Winter (p = 0.0354). There were no significant seasonal trends in Breslow thickness, ulceration, tumour infiltrating lymphocytes, or mitotic rate. Multivariate analysis showed that microsatellites were more likely to be diagnosed in the Winter (OR=2.00 (1.19–3.43), p = 0.010), lymphovascular invasion significantly more likely to be diagnosed in Autumn (OR=1.78 (1.16–2.76), p = 0.009), and perineural invasion was more likely to be diagnosed in the Summer (OR=0.44 (0.23–0.79), p = 0.007).
These data confirm that high-risk phenotypes are associated with increasing Breslow thickness and mitotic rate. However, season variability as an independent risk factor for the phenotypes is a novel finding.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients who receive immunotherapeutic drugs might develop an atypical response pattern, wherein they initially meet conventional response criteria for progressive disease but later have decreases in ...tumour burden. Such responses warrant further investigation into the potential benefits and risks for patients who continue immunotherapy beyond disease progression defined by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
For this pooled analysis, we included all submissions of trial reports and data to the US Food and Drug Administration (FDA) in support of marketing applications for anti-programmed death receptor-1 (PD-1) antibodies (alone or in combination) for the treatment of patients with unresectable or metastatic melanoma that allowed for continuation of the antibody beyond RECIST-defined progression in the anti-PD-1 group and were approved by FDA before Jan 1, 2017. To investigate the effect of treatment beyond progression in patients with metastatic melanoma and to better characterise which of these patients would benefit from extended treatment, we pooled individual patient data from patients who received at least one dose of an anti-PD-1 antibody in the included trials. We included any patient receiving the anti-PD-1 antibody after their RECIST-defined progression date in the treatment beyond progression cohort and analysed them descriptively at baseline and at time of progression versus the cohort not receiving treatment beyond progression. We analysed the target lesion response after progression in patients in the treatment beyond progression cohort relative to progressive disease and baseline target lesion burden. We defined a treatment beyond progression response as a decrease in target lesion tumour burden (sum of the reference diameters) of at least 30% from the burden at the time of RECIST-defined progression that did not require confirmation at a subsequent assessment. We also compared individual timepoint responses, overall survival, and adverse events in the treatment beyond progression versus no treatment beyond progression cohorts.
Among the eight multicentre clinical trials meeting this study's inclusion criteria, we pooled the data from 2624 patients receiving immunotherapy. 1361 (52%) had progressive disease, of whom 692 (51%) received continued anti-PD-1 antibody treatment beyond RECIST-defined progression and 669 (49%) did not. 95 (19%) of 500 patients in the treatment beyond progresssion cohort with evaluable assessments had a 30% or more decrease in tumour burden, when considering burden at RECIST-defined progression as the reference point, representing 14% of the 692 patients treated beyond progression and 4% of all 2624 patients treated with immunotherapy. Median overall survival in patients with RECIST-defined progressive disease given anti-PD-1 antibody was longer in the treatment beyond progression cohort (24·4 months, 95% CI 21·2–26·3) than in the cohort of patients who did not receive treatment beyond progression (11·2 months, 10·1–12·9). 362 (54%) of 669 patients in the no treatment beyond progression cohort had a serious adverse event up to 90 days after treatment discontinuation compared with 295 (43%) of 692 patients in the treatment beyond progression cohort. Immune-related adverse events that occurred up to 90 days from discontinuation were similar between the treatment beyond progression cohort (78 11% of 692 patients) and the no treatment beyond progression cohort (106 16% of 669).
Continuation of treatment beyond progression in the product labelling of these immunotherapies has not been recommended because the clinical benefit remains to be proven. Treatment beyond progression with anti-PD-1 antibody therapy might be appropriate for selected patients with unresectable or metastatic melanoma, identified by specific criteria at the time of progression, based on the potential for late responses in the setting of the known toxicity profile.
None.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Purpose People with a history of melanoma commonly report a fear of cancer recurrence (FCR), yet psychologic support is not routinely offered as part of ongoing melanoma care. This randomized ...controlled trial examined the efficacy of a psychoeducational intervention to reduce FCR and improve psychologic adjustment in this patient group compared with usual care. Methods The intervention comprised a newly developed psychoeducational resource and three telephone-based psychotherapeutic sessions over a 1-month period timed in accordance with dermatologic appointments. Participants were randomly assigned to intervention (n = 80) or usual care (n = 84). Assessments were completed at baseline, 1 month, and 6 months after dermatologic appointments. Linear mixed models were used to examine differences between treatment and control groups for patient-reported outcomes, including FCR, anxiety, stress, depression, melanoma-related knowledge, health behaviors, satisfaction with melanoma care, unmet needs, and health-related quality of life. Results At 6 months, the intervention group reported lower FCR severity, trigger, and distress scores than the control group in the baseline-adjusted models; the between-group mean difference was -1.9 for FCR severity (95% CI, -3.1 to -0.7; P = .002), -2.0 for FCR triggers (95% CI, -3.3 to -0.7; P = .003), and -0.7 for FCR distress (95% CI, -1.3 to -0.1; P = .03). The decrease in FCR severity (but not triggers or distress) remained statistically significant after adjustment for other covariates ( P = .04). At 6 months, the intervention group also reported lower stress (-1.6; 95% CI, -3.1 to -0.2; P = .03) and improved melanoma-related knowledge (1.7; 95% CI, 0.8 to 2.6; P < .001) compared with the control group. No differences were found between groups for other secondary outcomes. Conclusion This newly developed evidence-based psychoeducational intervention was effective in reducing FCR and stress and increasing melanoma-related knowledge in people at high risk for another melanoma.
The immunotherapeutic agent ipilimumab has helped address a significant unmet need in the treatment of advanced melanoma. Ipilimumab is a fully human monoclonal antibody that targets cytotoxic ...T‐lymphocyte antigen‐4 (CTLA‐4), thereby augmenting antitumor immune responses. After decades in which a number of clinical trials were conducted, ipilimumab was the first therapy to improve overall survival in a randomized, controlled phase III trial of patients with advanced melanoma. These results led to the regulatory approval of ipilimumab at 3 mg/kg for the treatment of unresectable or metastatic melanoma. More than 17,000 patients worldwide have received ipilimumab, either as a commercial drug at 3 mg/kg or in clinical trials and expanded access programs at different doses. Consistent with its proposed mechanism of action, the most common toxicities associated with ipilimumab therapy are inflammatory in nature. These immune‐related adverse events were mostly reversible when effective treatment guidelines were followed. Importantly, long‐term follow‐up of patients who received ipilimumab in a phase III trial showed that 24% survived at least two years, and in phase II studies, a proportion of patients survived at least five years. Evaluation of ipilimumab is ongoing in the adjuvant setting for melanoma, and for advanced disease in nonsmall cell lung, small cell lung, prostate, ovarian, and gastric cancers.
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BFBNIB, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
Cancer mutations generate novel (neo-)peptides recognised by T cells, but the determinants of recognition are not well characterised. The difference in predicted class I major histocompatibility ...complex (MHC-I) binding affinity between wild-type and corresponding mutant peptides (differential agretopicity index; DAI) may reflect clinically relevant cancer peptide immunogenicity. Our aim was to explore the relationship between DAI, measures of immune infiltration and patient outcomes in advanced cancer.
Cohorts of patients with advanced non-small-cell lung cancer (NSCLC; LUAD, n = 66) and melanoma (SKCM, n = 72) were obtained from The Cancer Genome Atlas. Three additional cohorts of immunotherapy treated patients with advanced melanoma (total n = 131) and NSCLC (n = 31) were analysed. Neopeptides and their clonal status were defined using genomic data. MHC-I binding affinity was predicted for each neopeptide and DAI values summarised as the sample mean DAI. Correlations between mean DAI and markers of immune activity were evaluated using measures of lymphocyte infiltration and immune gene expression.
In univariate and multivariate analyses, mean DAI significantly correlated with overall survival in 3/5 cohorts, with evidence of superiority over nonsynonymous mutational and neoantigen burden. In these cohorts, the effect was seen for mean DAI of clonal but not subclonal peptides. In SKCM, the association between mean DAI and survival bordered significance (P = 0.068), reaching significance in an immunotherapy-treated melanoma cohort (P = 0.003). Mean DAI but not mutational nor neoantigen burden was positively correlated with independently derived markers of immune infiltration in both SKCM (P = 0.027) and LUAD (P = 0.024).
The association between mean DAI, survival and measures of immune activity support the hypothesis that DAI is a determinant of cancer peptide immunogenicity. Investigation of DAI as a marker of immunologically relevant peptides in further datasets and future clinical studies of neoantigen based immunotherapies is warranted.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine nonmelanoma skin cancer, which is associated with the Merkel cell polyoma virus (MCPyV). Recently, expression of the terminal ...deoxynucleotidyl transferase (TdT) and the paired box gene 5 (PAX 5) has been consistently reported in the majority of MCCs. We tested 21 MCCs for the expression of MCPyV, TdT, PAX5, IgG, IgM, IgA, kappa, and lambda by immunohistochemistry and assessed IgH and Igk rearrangement in all 21 MCCs. All of the MCCs revealed specific expression of PAX5 and 72.8% of the MCCs expressed TdT. In addition, most of the MCCs revealed specific expression of one or more Ig subclasses and kappa or lambda. One MCC did reveal monoclonal IgH and Igk rearrangement next to two other MCCs showing Igk rearrangement. As coexpression of TdT and PAX5 under physiologic circumstances is restricted to pro/pre- and pre-B cells we propose, on the basis of our results, that the cell of origin of MCCs is a pro/pre- or pre-B cell rather than the postmitotic Merkel cells. MCPyV infection and transformation of pro-/pre-B cells are likely to induce the expression of simple cytokeratins as has been shown for SV40 in other nonepithelial cells. This model of cellular ancestry of MCCs might impact therapy and possibly helps to understand why approximately 20% of MCCs are MCPyV-negative.
For many solid tumors, immune checkpoint blockade therapy has become first line treatment, yet a large proportion of patients with immunologically cold tumors do not benefit due to the paucity of ...tumor infiltrating lymphocytes. Here we show that the orphan G Protein-Coupled Receptor 182 (GPR182) contributes to immunotherapy resistance in cancer via scavenging chemokines that are important for lymphocyte recruitment to tumors. GPR182 is primarily upregulated in melanoma-associated lymphatic endothelial cells (LECs) during tumorigenesis, and this atypical chemokine receptor endocytoses chemokines promiscuously. In GPR182-deficient mice, T cell infiltration into transplanted melanomas increases, leading to enhanced effector T cell function and improved antitumor immunity. Ablation of GPR182 leads to increased intratumoral concentrations of multiple chemokines and thereby sensitizes poorly immunogenic tumors to immune checkpoint blockade and adoptive cellular therapies. CXCR3 blockade reverses the improved antitumor immunity and T cell infiltration characteristic of GPR182-deficient mice. Our study thus identifies GPR182 as an upstream regulator of the CXCL9/CXCL10/CXCR3 axis that limits antitumor immunity and as a potential therapeutic target in immunologically cold tumors.
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