Distinct sets of molecular characteristics define tumor-rejecting neoantigens.

Challenges in identifying tumor-rejecting neoantigens limit the efficacy of neoantigen vaccines to treat cancers, including cutaneous squamous cell carcinoma (cSCC). A minority of human cSCC tumors shared neoantigens, supporting the need for personalized vaccines. Using a UV-induced mouse cSCC model which recapitulated the mutational signature and driver mutations found in human disease, we found that CD8 T cells constrain cSCC. Two MHC class I neoantigens were identified that constrained cSCC growth. Compared to the wild-type peptides, one tumor-rejecting neoantigen exhibited improved MHC binding and the other had increased solvent accessibility of the mutated residue. Across known neoantigens that do not impact MHC binding, structural modeling of the peptide/MHC complexes indicated that increased solvent accessibility, which will facilitate TCR recognition of the neoantigen, distinguished tumor-rejecting from non-immunogenic neoantigens. This work reveals characteristics of tumor-rejecting neoantigens that may be of considerable importance in identifying optimal vaccine candidates in cSCC and other cancers.

Major histocompatibility complex class II in the tumor microenvironment: functions of nonprofessional antigen-presenting cells.

Major histocompatibility complex class-II-restricted presentation by nonprofessional antigen-presenting cells in the tumor microenvironment can regulate antitumor T-cell responses. In murine models, tumor cell-specific MHC class II expression decreases in vivo tumor growth, dependent on T cells. Tumor cell-specific MHC class II expression is associated with improved survival and response to immune checkpoint inhibitors in human cancers. Antigen-presenting cancer-associated fibroblasts (apCAF) present MHC class-II-restricted antigens and activate CD4 T cells. The role of MHC class II on apCAFs depends on the cell of origin. MHC class II on tumoral lymphatic endothelial cells leads to expansion of regulatory T cells and increased in vivo tumor growth.

High GILT Expression Is Associated with Improved Survival in Metastatic Melanoma Patients Treated with Immune Checkpoint Inhibition.

Gamma-interferon-inducible lysosomal thiol reductase (GILT) is critical for MHC class II restricted presentation of multiple melanoma antigens. There is variable GILT protein expression in malignant melanocytes in melanoma specimens. High GILT mRNA expression in melanoma specimens is associated with improved overall survival, before the advent of immune checkpoint inhibitors (ICI). However, the association of GILT in metastatic melanoma with survival in patients treated with ICI and the cell type expressing GILT associated with survival have not been determined. Using RNA sequencing datasets, high GILT mRNA expression in metastatic melanoma specimens was associated with improved progression-free and overall survival in patients treated with ICI. A clinical dataset of metastatic melanoma specimens was generated and annotated with clinical information. Positive GILT immunohistochemical staining in antigen presenting cells and melanoma cells was observed in 100% and 65% of metastatic melanoma specimens, respectively. In the subset of patients treated with ICI in the clinical dataset, high GILT protein expression within melanoma cells was associated with improved overall survival. The association of GILT mRNA and protein expression with survival was independent of cancer stage. These studies support that high GILT mRNA expression in bulk tumor samples and high GILT protein expression in melanoma cells is associated with improved survival in ICI-treated patients. These findings support further investigation of GILT as a biomarker to predict the response to ICI.

Synovial Fluid Cytokine Profile at the Time of Arthroscopy Explains Intermediate-Term Functional Outcomes.

BACKGROUND: The intra-articular immune response after ligamentous, meniscal, or focal chondral knee injuries likely plays a role in intra-articular healing and the onset and progression of posttraumatic osteoarthritis. PURPOSE: To evaluate the association of synovial fluid cytokine concentrations measured at the time of knee arthroscopy with intermediate-term functional outcomes after knee arthroscopy based on the Lysholm score. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This was a prospective cohort study of patients undergoing arthroscopic knee surgery. Synovial fluid was aspirated from the injured knee immediately before surgical incision, and the concentrations of 10 cytokines were analyzed using immunoassay. Principal component regression was used to create a model to predict patient-reported Lysholm score at a minimum of 5 years postoperatively. Hierarchical clustering was performed to identify groups of patients with similar synovial fluid inflammatory phenotypes. Lysholm scores and cytokine concentrations were compared between clusters. RESULTS: A total of 26 patients (mean age, 40.33 ± 16.40 years) were included in the analysis. The mean duration between surgery and follow-up was 6.69 ± 0.72 years. A model consisting of 2 principal components (PC1, PC2) explained 62.48% of the variance in the cytokine data and 52.03% of the variance in intermediate-term Lysholm score. Hierarchical clustering resulted in 3 patient clusters based on the principal components used in the regression model. Despite no baseline differences in Lysholm score, cluster 3 demonstrated significantly greater intermediate-term Lysholm score compared with cluster 2 (94.33 vs 76.09, respectively; 95% CI, 5.96-30.52; P = .006) and cluster 1 (94.33 vs 52.33, respectively; 95% CI, 24.09-59.91; P = .003). Cluster 3, when compared with the overall means, was characterized by greater PC1 value (1.01 vs 0.00, respectively; P = .030) and greater PC2 value (0.86 vs 0.00, respectively; P = .002). CONCLUSION: The concentrations of select synovial fluid cytokines assessed at the time of knee arthroscopy can be used to explain more than half of the variance in intermediate-term functional outcomes.

Intravenous Ketamine Infusion as an Adjunctive Pain Treatment for Erythromelalgia: A Pediatric Case Report.

Erythromelalgia is a rare neurovascular pain condition characterized by erythematous, warm, and painful extremities. Symptoms are exacerbated by heat and relieved by cooling. Treatment is challenging and focuses on symptom control with various medications and therapies targeted toward eliminating destructive cooling behaviors. This pediatric case was notable because the patient's pain dramatically improved after a short-term, low-dose ketamine infusion, allowing her to finally wean off detrimental cooling practices of her extremities. Intravenous ketamine has rarely been described as an adjunctive analgesic strategy for erythromelalgia.

Physachenolide C induces complete regression of established murine melanoma tumors via apoptosis and cell cycle arrest.

Melanoma is an aggressive skin cancer that metastasizes to other organs. While immune checkpoint blockade with anti-PD-1 has transformed the treatment of advanced melanoma, many melanoma patients fail to respond to anti-PD-1 therapy or develop acquired resistance. Thus, effective treatment of melanoma still represents an unmet clinical need. Our prior studies support the anti-cancer activity of the 17ß-hydroxywithanolide class of natural products, including physachenolide C (PCC). As single agents, PCC and its semi-synthetic analog demonstrated direct cytotoxicity in a panel of murine melanoma cell lines, which share common driver mutations with human melanoma; the IC50 values ranged from 0.19-1.8 µM. PCC treatment induced apoptosis of tumor cells both in vitro and in vivo. In vivo treatment with PCC alone caused the complete regression of established melanoma tumors in all mice, with a durable response in 33% of mice after discontinuation of treatment. T cell-mediated immunity did not contribute to the therapeutic efficacy of PCC or prevent tumor recurrence in YUMM2.1 melanoma model. In addition to apoptosis, PCC treatment induced G0-G1 cell cycle arrest of melanoma cells, which upon removal of PCC, re-entered the cell cycle. PCC-induced cycle cell arrest likely contributed to the in vivo tumor recurrence in a portion of mice after discontinuation of treatment. Thus, 17ß-hydroxywithanolides have the potential to improve the therapeutic outcome for patients with advanced melanoma.

Shared Gene Expression and Immune Pathway Changes Associated with Progression from Nevi to Melanoma.

There is a need to identify molecular biomarkers of melanoma progression to assist the development of chemoprevention strategies to lower melanoma incidence. Using datasets containing gene expression for dysplastic nevi and melanoma or melanoma arising in a nevus, we performed differential gene expression analysis and regularized regression models to identify genes and pathways that were associated with progression from nevi to melanoma. A small number of genes distinguished nevi from melanoma. Differential expression of seven genes was identified between nevi and melanoma in three independent datasets. C1QB, CXCL9, CXCL10, DFNA5 (GSDME), FCGR1B, and PRAME were increased in melanoma, and SCGB1D2 was decreased in melanoma, compared to dysplastic nevi or nevi that progressed to melanoma. Further supporting an association with melanomagenesis, these genes demonstrated a linear change in expression from benign nevi to dysplastic nevi to radial growth phase melanoma to vertical growth phase melanoma. The genes associated with melanoma progression showed significant enrichment of multiple pathways related to the immune system. This study demonstrates (1) a novel application of bioinformatic approaches to aid clinical trials of melanoma chemoprevention and (2) the feasibility of determining a gene signature biomarker of melanomagenesis.

Management and outcomes of primary anorectal melanoma in the United States.

Aims: To analyze outcomes in primary anorectal melanoma, a rare disease with limited data and treatment guidelines. Materials & methods: We analyzed 305 subjects in the National Cancer Database from 2004 to 2015. The primary end point was overall survival (OS). Results: Surgery was predictive of OS (median 2.24 vs 1.18 years; p = 0.009) with no survival difference between local and transabdominal approaches (p = 0.77). No OS benefit was seen with chemotherapy (p = 0.16), radiotherapy (p = 0.31) or adjuvant therapy post surgery (p > 0.05 for all groups). Targeted therapy trended toward higher survival in metastatic patients (1.33 vs 0.55 years; p = 0.06). Conclusion: In nonmetastatic patients, surgery of any method is associated with a survival benefit. The trend for improved survival following targeted therapy in metastatic patients merits further exploration.