CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T_reg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). T_reg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8⁺ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.

Summary: Immune checkpoint receptors and ligands such as cytotoxic T lymphocyte antigen‐4 (CTLA‐4), programmed death‐1 (PD‐1) and ligand‐1 (PD‐L1) are widely expressed on immune and non‐immune cells and fine tune the activation level of immune cells, thus, enabling, preventing, or terminating immune responses. Blockade of CTLA‐4, PD‐1 or PD‐L1 by checkpoint inhibitors (CIs), unleashing immune responses, has become a mainstay in the treatment of diverse types of cancer. The induction of autoinflammatory, yet unspecific tissue damage in diverse organs is called an immune related adverse event (irAE), a class side‐effect of CIs and may require the discontinuation of immunotherapy. Among frequent skin rashes, CIs targeting the PD‐L1/PD‐1 axis can elicit the IgG autoantibody‐ and granulocyte‐driven bullous pemphigoid (BP) in about 0.3% to 0.6% of treated patients. Pathogenesis of BP requires a complex cellular inflammatory response after anti‐BP180 autoantibody binding to the dermal epidermal junction. The prevalence of autoantibodies against BP180 in healthy blood donors of approximately 0.52% equals the prevalence of irBP among treated cancer patients, underlining the potential relevance of the PD‐1 mediated regulation of tissue inflammation for spontaneous BP. If skin rashes appear during CI therapy, biopsies should be taken and examined by histopathological and direct immunofluorescence microscopy.

Intravenous immunoglobulin (IVIg) contains pooled immunoglobulins from the plasma of healthy blood donors. All plasma samples are tested for HIV, hepatitis viruses (A, B, and C), and parvovirus B19. As part of this screening step, nucleic acid amplification technology (NAT) is used and allows the presence of specific antibodies targeting viral structures that are commonly used to test for infection status, such as anti‐hepatitis B surface antigen (HBs) or anti‐hepatitis B virus core (HBc) antibodies. For this reason, manufacturers point to the possibility of false‐positive viral serological test results following IVIg treatment due to the passive transfer of antibodies. IVIg therapy is commonly used to manage patients with severe, treatment‐refractory autoimmune skin diseases. The aim of this cohort study was to retrospectively quantify newly‐discovered positive serological HBV test results after IVIg treatment in patients with autoimmune skin diseases. Between March 2018 and June 2021, 28 patients with autoimmune skin diseases received IVIg therapy, of whom 17 were longitudinally followed‐up. None of the patients had evidence of active HBV infection prior to IVIg therapy. All patients (n = 17) had detectable anti‐HBs antibodies and 12 patients had anti‐HBc antibodies 4 weeks after commencing IVIg treatment. Passive antibody transfer seems the most likely interpretation. Nevertheless, complete serological hepatitis assessment should be performed to exclude a new infection. We recommend hepatitis screening before IVIg therapy to prevent diagnostic confusion which may arise due to passive antibody transfer.

Mucous membrane pemphigoid (MMP) is a mucocutaneous autoimmune blistering disease affecting diverse mucous membranes and the skin with inflammatory blisters and erosions. The pathogenesis of MMP is only poorly understood, but inflammation in MMP is triggered by specific binding of autoantibodies directed to different proteins of the dermal-epidermal/-epithelial junction, subsequently leading to the influx of inflammatory cells, particularly neutrophils, into the dermis. Using the anti-laminin 332 antibody transfer model of MMP, we addressed the molecular mechanisms of neutrophil infiltration and its significance for the eruption of mucocutaneous lesions. Mice deficient in 5-lipoxygenase ( Alox5 ^–/– ) or in the leukotriene B ₄ (LTB ₄ ) receptor BLT1 ( Ltb4r1 ^–/– ) were resistant to skin inflammation and exhibited substantially fewer mucosal lesions, with deficiency in either gene compromising the recruitment of neutrophils to the lesion. Furthermore, neutrophil-specific genetic deficiency in Ltb4r1 similarly protected from MMP. Hence, BLT1 was required on neutrophils, and neutrophil recruitment was indispensable for the eruption of lesions in MMP. In line with these findings, the BLT1 inhibitor CP-105,606 ameliorated MMP dose-dependently. Collectively, our results highlight neutrophils and LTB ₄ /BLT1 as key drivers of inflammation in MMP and as promising therapeutic targets.

Zusammenfassung: Immuncheckpoint‐Rezeptoren und ‐Liganden wie das cytotoxic T‐lymphocyte‐associated Protein 4 (CTLA‐4), programmed death‐1 (PD‐1) und ligand‐1 (PD‐L1) werden sowohl auf Immun‐ als auch auf nicht‐Immunzellen in großem Umfang exprimiert und dienen der Feinabstimmung des Aktivierungsniveaus von Immunzellen, wodurch Immunreaktionen ermöglicht, verhindert oder beendet werden. Die Blockade von CTLA‐4, PD‐1 oder PD‐L1 durch Checkpoint‐Inhibitoren (CI) entfesselt Immunreaktionen und ist zu einer tragenden Säule bei der Behandlung verschiedener Krebsarten geworden. Die Induktion autoinflammatorischer, jedoch unspezifischer Gewebeschäden in verschiedenen Organen wird als immunbedingte unerwünschte Wirkung ( immune related adverse event , irAE) bezeichnet, eine klassentypische Nebenwirkung der CI, die den Abbruch der Immuntherapie erfordern kann. Unter den häufig auftretenden Hautausschlägen können CI, die auf die PD‐L1/PD‐1‐Achse abzielen, bei etwa 0,3% bis 0,6% der behandelten Patienten das durch IgG‐Autoantikörper und Granulozyten hervorgerufene bullöse Pemphigoid (BP) auslösen. Die Pathogenese des BP erfordert eine komplexe zelluläre Entzündungsreaktion nach Bindung von Anti‐BP180‐Autoantikörpern an die dermo‐epidermale Junktion. Die Prävalenz von Autoantikörpern gegen BP180 bei gesunden Blutspendern von etwa 0,52% entspricht der Prävalenz von irBP bei behandelten Krebspatienten, was die potenzielle Bedeutung der PD‐1‐vermittelten Regulierung der Entzündungsreaktion im Gewebe beim spontanen BP unterstreicht. Wenn unter der Checkpoint‐Inhibitor‐Therapie Hautreaktionen auftreten, sollten Biopsien entnommen und durch histopathologische und direkte Immunfluoreszenzmikroskopie untersucht werden.

Annular lichen planus is a rare clinical variant of the lichen planus presenting with round–oval, red to brown macules and plaques with no central atrophy and slightly raised, nonscaly borders. Histopathological features are indistinguishable from typical lichen planus. Given that the accurate diagnosis relies on both the clinical presentation and typical histological features, it is important to be aware of the clinical spectrum of lichen planus.