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Neuropeptide Y (NPY) increases survival in experimental septic shock, which might be mediated by cardiovascular and/or immunological effects. To study the latter hypothesis, we monitored blood leukocyte subsets over 96 h after intravenous (i.v.) application of LPS in chronically i.v.-cannulated rats. LPS induced a dramatic leukopenia at 4 h after challenge, which was blunted in NPY-treated animals by stabilizing granulocyte and T-lymphocyte numbers. In addition, NPY treatment prevented tissue immigration of monocytes at early time points and consecutively mobilized activated monocytes from the third day after challenge. RT-PCR and in vitro adhesion studies provided evidence for a NPY Y2 receptor-mediated effect on monocytes. Thus, NPY treatment has profound receptor-specific effects on the migration and adhesion of leukocytes under endotoxemic conditions. [Copyright &y& Elsevier]

Objectives: Age dependent secretion of testicular and adrenal androgens was examined in healthy men and patients with erectile dysfunction (ED).Methods: In 95 healthy men (age 20–74 years) and 739 patients with ED, luteineizing hormone (LH, n=739), adrenocorticotropic hormone (ACTH, n=480) and the secretion products of testis and adrenal gland testosterone (T, n=750), free testosterone (fT, n=718), dehydroepiandrosteronesulfate (DHEAS, n=598) and cortisol (n=538) were measured.Results: In healthy men, LH was measured from 0.75–8.58 mlU/ml and ACTH from 10.59–121.7 pg/ml. Statistically, age was not correlated to LH (P=0.573) and ACTH (P=0.833) in healthy men. The secretion products T (P<0.05), fT (P<0.001), DHEAS (P<0.001) and cortisol (P<0.05) declined significantly with age in healthy persons. In patients with ED, a significant age dependent increase of LH (P<0.05, n=739), but not ACTH (P=0.469, n=480) was found. T (P<0.001, n=736), fT (P<0.001, n=718) and DHEAS (P<0.001, n=598), but not cortisol (P=0.307, n=538) declined in age dependent patients with ED. Age matching revealed a statistical significant elevation (P<0.05) only for LH (n=659) in comparison to healthy men (n=94), all other hormones were not different in both groups. Conclusion: An LH-increase in patients with erectile dysfunction underlines the importance of Leydig cell degeneration in this disease, but age dependent decline of T secretion was comparable to healthy men, demonstrating a working hypophyseal–testicular-axis. Indication of androgen replacement is therefore limited to selected cases. [ABSTRACT FROM AUTHOR]

Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies. • Comparison of different endogenous target antigens for adoptive T cell therapy • Melanoma immune escape phenotype determined by class and level of target antigen • Targeting melanosomal antigens drives dedifferentiation and myeloid infiltration • Persistence of oncogenic antigen allows for salvage immune checkpoint therapy Using mouse models of melanoma, Effern et al. demonstrate how the choice of target antigens for adoptive T cell therapy determines resistance mechanisms. Targeting melanosomal antigens promotes decreased antigen expression through melanoma dedifferentiation with myeloid cell infiltration, whereas targeting oncogenic CDK4R24C results in antigen persistence, allowing for salvage immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Although adoptive T‐cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour‐specific T cells. T‐cell‐specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2‐deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER‐2 increased the activation of the Src family kinase LCK and cytokine‐induced STAT‐5 signalling, thereby enhancing both CAR T‐cell activation and homing to CXCL9/10‐expressing tumours to eradicate HER‐2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T‐cell‐mediated anti‐tumour immunity and CAR T‐cell therapy against solid tumours. Synopsis: This study reveals a role for protein tyrosine phosphatase N2 (PTPN2) in cancer immunosurveillance and T‐cell infiltration into solid tumours. Antagonizing PTPN2 thus represents a promising therapeutic strategy for adoptive T‐cell therapy. T‐cell‐specific PTPN2 deletion prevents tumour formation in p53+/− mice without exacerbating inflammation.PTPN2 deletion enhances LCK‐mediated CAR T‐cell cytotoxicity.PTPN2 deletion promotes STAT5‐mediated CXCR3 expression and CAR T‐cell homing.PTPN2‐deficient CAR T cells eradicate solid tumours in vivo.PTPN2 inhibition enhances the activity of human CAR T cells. [ABSTRACT FROM AUTHOR]

Objective: The immune system can halt cancer progression by suppressing outgrowth of clinically occult micrometastases in a state of cancer‐immune equilibrium. Cutaneous melanoma provides a unique opportunity to study the immune contexture of such lesions, as miniscule skin metastases are accessible to clinical inspection and diagnostic biopsy. Methods: Here, we analysed by multiplex immunofluorescence microscopy samples from a melanoma patient presenting with an overt and an occult in‐transit metastasis (ITM), the latter of which appeared as a small erythematous papule. Results: Microarchitecture and immune composition in the two lesions were vastly different. CD4+ and CD8+ T cells accumulated around the margin of the overt SOX10+ Melan A+ ITM but were largely excluded from the tumor centre. By contrast, the occult micrometastasis contained only few SOX10+ Melan A− melanoma cells which were scattered within a dense infiltrate of T cells, including a prominent population of CD103+ CD8+ T cells resembling tissue‐resident memory T (TRM) cells. Notably, almost every single melanoma cell in the micrometastasis was in close proximity to these TRM‐like cells. Conclusion: Such results support the emerging concept that CD103+ CD8+ TRM cells are key mediators of cancer surveillance and imply an important function of these cells in controlling clinically occult micrometastases in humans. [ABSTRACT FROM AUTHOR]