Search

Checkpoint inhibitors treat a variety of tumor types with significant benefits. Unfortunately, these therapies come with diverse adverse events. Skin rash is observed early into treatment and might serve as an indicator of downstream responses to therapy. We studied the cellular composition of cutaneous eruptions and whether their contribution varies with the treatment applied. Skin samples from 18 patients with cancer and 11 controls were evaluated by mono- and multiplex imaging, quantification, and statistical analysis. T cells were the prime contributors to skin rash, with T cells and macrophages interacting and proliferating on site. Among T cell subsets examined, type 1 and 17 T cells were relatively increased among inflammatory skin infiltrates. A combination of increased cytotoxic T cell content and decreased macrophage abundance was associated with dual checkpoint inhibition over PD1 inhibition alone. Importantly, responders significantly separated from nonresponders by greater CD68+ macrophage and either CD11c+ antigen-presenting cell or CD4+ T cell abundance in skin rash. The microenvironment promoted epidermal proliferation and thickening as well. The combination of checkpoint inhibitors used affects the development and composition of skin infiltrates, whereas the combined abundance of two cell types in cutaneous eruptions aligns with responses to checkpoint inhibitor therapy.

Otoferlin mRNA expression is increased in JDM patients’ PBMCs and muscle compared to healthy controls. This study aims to evaluate the role of otoferlin in JDM disease pathophysiology and its association with disease activity in untreated children with JDM. A total of 26 untreated JDM (88.5% female, 92.3% white, non-Hispanic) and 15 healthy controls were included in this study. Otoferlin mRNA expression was determined by qRT-PCR before and a few months after therapy. Detailed flow cytometry of various cell surface markers and cytoplasmic otoferlin was performed to identify cells expressing otoferlin. In addition, muscle otoferlin expression was evaluated in situ in six untreated JDM patients and three healthy controls. There was a significant increase in otoferlin expression in JDM children compared to controls (Median 67.5 vs. 2.1; p = 0.001). There was a positive correlation between mRNA otoferlin expression and the following disease activity markers: disease activity scores (DAS)-total (rs = 0.62, p < 0.001); childhood myositis assessment scale (CMAS) (rs = −0.61, p = 0.002); neopterin (rs = 0.57, p = 0.004) and von Willebrand factor antigen (vWF: Ag) (rs = 0.60, p = 0.004). Most of the otoferlin-positive cells were unswitched B cells (63–99.4%), with 65–75% of them expressing plasmablast markers (CD19+, IgM+, CD38hi, CD24−). The findings of this pilot study suggest that otoferlin expression is associated with muscle weakness, making it a possible biomarker of disease activity. Additionally, B cells and plasmablasts were the primary cells expressing otoferlin.

Mutations underlying disease in tuberous sclerosis complex (TSC) give rise to tumors with biallelic mutations in TSC1 or TSC2 and hyperactive mammalian target of rapamycin complex 1 (mTORC1). Benign tumors might exhibit de novo expression of immunogens, targetable by immunotherapy. As tumors may rely on ganglioside D3 (GD3) expression for mTORC1 activation and growth, we compared GD3 expression in tissues from patients with TSC and controls. GD3 was overexpressed in affected tissues from patients with TSC and also in aging Tsc2+/– mice. As GD3 overexpression was not accompanied by marked natural immune responses to the target molecule, we performed preclinical studies with GD3 chimeric antigen receptor (CAR) T cells. Polyfunctional CAR T cells were cytotoxic toward GD3-overexpressing targets. In mice challenged with Tsc2–/– tumor cells, CAR T cells substantially and durably reduced the tumor burden, correlating with increased T cell infiltration. We also treated aged Tsc2+/– heterozygous (>60 weeks) mice that carry spontaneous Tsc2–/– tumors with GD3 CAR or untransduced T cells and evaluated them at endpoint. Following CAR T cell treatment, the majority of mice were tumor free while all control animals carried tumors. The outcomes demonstrate a strong treatment effect and suggest that targeting GD3 can be successful in TSC.

Cytokines are key molecules within the tumor microenvironment (TME) that can be used as biomarkers to predict the magnitude of anti-tumor immune responses. During immune monitoring, it has been customary to predict outcomes based on the abundance of a single cytokine, in particular IFN-γ or TGF-β, as a readout of ongoing anti-cancer immunity. However, individual cytokines within the TME can exhibit dual opposing roles. For example, both IFN-γ and TGF-β have been associated with pro- and anti-tumor functions. Moreover, cytokines originating from different cellular sources influence the crosstalk between CD4+ and CD8+ T cells, while the array of cytokines expressed by T cells is also instrumental in defining the mechanisms of action and efficacy of treatments. Thus, it becomes increasingly clear that a reliable readout of ongoing immunity within the TME will have to include more than the measurement of a single cytokine. This review focuses on defining a panel of cytokines that could help to reliably predict and analyze the outcomes of T cell-based anti-tumor therapies.