Activity

Neuroblastoma (NB) still remains a major challenge in pediatric oncology. We recently showed CD11b+-dependent upregulation of the PD-1/PD-L1 checkpoint on NB cells treated with the chimeric anti-GD2 antibody (Ab) ch14.18/CHO. Here, we report effects of reduction of CD11b+ myeloid suppressive cells on ch14.18/CHO immunotherapy against NB. Flow cytometry, immunohistochemistry and RT-PCR were used to assess tumor infiltrating leukocytes and expression of myeloid suppressive cell-associated genes. XTT assay was used to show impact of 5-FU on tumor and effector cells. Antitumor effects of the combined treatment with ch14.18/CHO and reduction of myeloid suppressive cells were evaluated in a syngeneic NB mouse model. Tumor tissue of untreated mice showed a strong infiltration by CD11b+ cells (53% of all tumor infiltrating leukocytes). RT-PCR analysis of tumors revealed strong expression of the myeloid suppressive cell-associated genes analyzed with the strongest induction of M-CSFr, CCL2, IL-1β, IL-4, IL-6 r, IL-8, Arg1, and NOS2. Compared to controls, application of anti-CD11b Ab resulted in reduction of both CD11b+ cells in tumors and expression of myeloid suppressive cell-associated genes as well as delayed tumor growth and prolonged survival. These effects could be further improved by 5-FU. Importantly, the combinatorial immunotherapy with ch14.18/CHO and 5-FU showed the strongest antitumor effects and superior survival rates. In conclusion, reduction of immune suppressive myeloid cells augments anti-NB efficacy of a ch14.18/CHO-based immunotherapy representing a new effective treatment strategy against GD2-positive cancers.Antibodies targeting the co-inhibitory receptor programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand CD274 (best known as PD-L1) have shown some activity in patients with metastatic triple-negative breast cancer (TNBC), especially in a recent Phase III clinical trial combining PD-L1 blockade with taxane-based chemotherapy. Despite these encouraging findings, however, most patients with TNBC fail to derive significant benefits from PD-L1 blockade, calling for the identification of novel therapeutic approaches. Here, we used the 4T1 murine mammary cancer model of metastatic and immune-resistant TNBC to test whether focal radiation therapy (RT), a powerful inducer of immunogenic cell death, in combination with various immunotherapeutic strategies can overcome resistance to immune checkpoint blockade. Our results suggest that focal RT enhances the therapeutic effects of PD-1 blockade against primary 4T1 tumors and their metastases. Similarly, the efficacy of an antibody specific for V-set immunoregulatory receptor (VSIR, another co-inhibitory receptor best known as VISTA) was enhanced by focal RT. Administration of cyclophosphamide plus RT and dual PD-1/VISTA blockade had superior therapeutic effects, which were associated with activation of tumor-infiltrating CD8+ T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells (MDSCs). Overall, these results demonstrate that RT can sensitize immunorefractory tumors to VISTA or PD-1 blockade, that this effect is enhanced by the addition of cyclophosphamide and suggest that a multipronged immunotherapeutic approach may also be required to increase the incidence of durable responses in patients with TNBC.CD4+Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment restrain antitumor immunity, resulting in tumor aggression and poor survival in hepatocellular carcinoma (HCC). CD8+CD122+ Tregs have been previously shown to be more potent in immunosuppression than are CD4+Foxp3+ Tregs. Previous studies have demonstrated that resveratrol exerts its anti-cancer effects by downregulating CD4+Foxp3+ and M2-like macrophages, two key immunoregulatory cells that maintain the immunosuppressive tumor microenvironment. In this study, we found that resveratrol inhibited the tumor growth in a subcutaneous Hepa1-6 HCC model and decreased the frequency of CD8+CD122+ Tregs in the tumor as well as lymph nodes and spleen of the tumor-bearing mice. It also increased the percentage of IFN-γ-expressing CD8+ T cells in the tumor and peripheral lymphoid organs. The antitumor effects of resveratrol were partially reversed by the adoptive transfer of exogenous CD8+CD122+ Tregs into the tumor-bearing mice. Meanwhile, resveratrol treatment downregulated immunosuppressive cytokines, including TGF-β1 and interleukin-10, in the tumor while elevating antitumor cytokines, TNF-α and IFN-γ. It also inhibited the activation of STAT3 signaling in the tumor. C1632 supplier As expected, resveratrol reduced the percentage of M2-like macrophages in the mice. Importantly, resveratrol suppressed orthotopic H22 tumor growth and decreased the frequency of CD8+CD122+ Tregs and M2-like macrophages in the tumor-bearing mice. Furthermore, our studies showed that resveratrol, at non-cytotoxic concentrations, inhibited CD8+CD122+ Treg differentiation from CD8+CD122- T cells in vitro. Thus, our studies unveiled a new immune mechanism underlying the immunosuppressive tumor microenvironment and demonstrated that resveratrol could help reverse it by diminishing CD8+CD122+ Tregs.

Congenital triangular alopecia (CTA) is a benign, asymptomatic, nonprogressive, localized and noncicatricial type of alopecia that is usually first noted during infancy or childhood. The pattern of hair loss is traditionally described as triangular, oval or lancet shaped with apex toward the vertex.

We present a case series of CTA located in unusual sites.

We performed trichoscopy in 78 patients with CTA. From this group, we selected 10 individuals (4 males and 6 females) whose disease was not localized on the typical scalp area.

The alopecic area was located on the occipital region in 5 patients, the parietal region in 4 patients, at the vertex in 1. With trichoscopy, vellus hairs were detected in all patients, and evidence of empty follicles was noticed only in 3 patients.

In contrast with the preconceived notion that all CTAs are frontotemporal, our case series points out that this disease could be localized in other scalp sites.

In contrast with the preconceived notion that all CTAs are frontotemporal, our case series points out that this disease could be localized in other scalp sites.