Diana Dudziak

Characterizing the non-pathological, exercise-induced immune-metabolic stress regulation is important for understanding physiological adaptations and distinguishing them from maladaptive responses. Because such responses are mostly studied with extensive, resource-intensive protocols, simple, standardized tests eliciting measurable immune-metabolic responses are valuable in clinical and non-clinical settings. Established field tests assess functional exercise capacity rather than providing a standardized stimulus for investigating exercise-induced immune regulation. This study examined the effects of the 1-minute sit-to-stand test (STST) on immune-metabolic stress indices and whether it elicits sufficient anaerobic stress to serve as a tool for investigating exercise-induced immunological stress responses. Capillary blood from 28 healthy adults was collected before, immediately after, and during 45 min after exercise to determine lactate, glucose, and blood cell counts; hemoconcentration correction was applied. Lactate increased significantly immediately after the STST, exceeding the anaerobic threshold (> 4 mmol/L). Leukocyte, lymphocyte, and granulocyte counts rose significantly post-exercise; leukocytes returned to baseline by 30 min, whereas granulocytes remained elevated. GLR and SII decreased significantly immediately post-exercise and increased during recovery, together with SIRI. Lactate changes correlated significantly with leukocyte, lymphocyte and granulocyte changes. Therefore, the STST represents a practical, standardized field-based model for immune-metabolic assessment with translational potential for clinical and non-clinical settings.

Chronic immune-mediated peripheral nerve myelinopathies (CIPNM) are progressive and debilitating disorders that can be refractory to current treatment regimes. The bispecific T-cell engager (BiTE) teclistamab depletes B-cell Maturation Antigen (BCMA) positive late-stage B- cells and plasma cells by engaging T-cells. We present two patients with treatment-refractory CIPNM (Patient 1: IgM-kappa-associated CIPNM, follow-up 9 months; Patient 2: Anti-myelin-associated-glycoprotein (MAG) antibody-mediated CIPNM, follow-up 6 months). Both patients are characterized by rapid improvement upon treatment with teclistamab: substantially increased walking distance, accompanied by reduced nerve swelling and markedly improved electroneurography. Furthermore, some nerves without stimulus response at baseline are showing detectable response during follow-up. The functional recovery of peripheral nerves is paralleled by decreased serum neurofilament levels, indicating reduced neuronal damage. IgM kappa paraprotein and high-titer MAG antibodies are undetectable 6 weeks after the first dose of teclistamab and remain negative throughout the follow-up, whereas soluble BCMA re-emerges following an initial reduction. No serious adverse events are observed during treatment. This case series highlights the significant therapeutic potential of teclistamab in treatment-refractory CIPNM and provides an important example of ‘off-the-shelf’ BiTE therapy being well tolerated and effective and should be further investigated in neuro-immunological disorders.

Bispecific antibodies are used for the treatment of hematological malignancies as well as solid tumors. One of their main effector mechanisms is the recruitment of effector cells such as CD8⁺ T cells and CD16A⁺ NK cells to tumor cells. Bispecific innate cell engagers (ICE®) harnessing CD16A⁺ NK cells have been shown to induce significant tumor cell lysis in preclinical models, translating to promising signs of clinical activity together with a well-managed safety profile. However, how killing of tumor cells by NK cells influences other innate immune cells in the tumor microenvironment, such as dendritic cells (DCs), instrumental in bridging innate and adaptive tumor immunity, is largely unknown. Thus, we here analyzed whether antibody-dependent cell-mediated cytotoxicity by NK cells affected human DC subpopulations. We could show that killing of tumor cells leads to a strong activation of human conventional DCs type 1 (cDC1), DC2, and DC3 with enhanced expression of co-stimulatory molecules as well as the secretion of proinflammatory cytokines. Further, DC subpopulations as well as surviving tumor cells showed increased expression of the immunoregulatory molecule PD-L1 that is known to dampen T-cell immunity. Nevertheless, ADCC boosted the capacity of cDC1 and DC2 to prime naïve T cell responses but not of DC3. Thus, our data suggests that the therapy with bispecific antibodies targeting NK cells may have the potential to facilitate adaptive antitumor immune responses via activation of cDC1 and DC2.

Tumor-associated macrophages (TAMs) dynamically influence anti-tumor immunity. Understanding TAM function is therefore critical to design immunotherapies. By combining syngeneic models of colorectal and pancreatic cancer with cell type-specific deletion of the epithelial-to-mesenchymal transition driver Zeb1, which is expressed in subsets of TAMs, we discovered that ZEB1 is an intrinsic regulator of TAM-controlled T cell trafficking and anti-tumor immune responses. ZEB1 supports secretion of a subset of chemokines via the constitutive pathway, including CXCL10, CCL2 and CCL22, by regulating their biosynthesis, vesicular transport and release. This elevates cytotoxic T cell (CTL) recruitment in vitro and fosters immunosurveillance by CTLs in tumors and metastases as well in an organotypic model for therapeutic CD8 + T cell addition. Our study identifies ZEB1 in TAMs as a facilitator of anti-tumor immunity, suggests a window of opportunity for cytokine-guided CTL tropism and reinforces the importance of onco-immunological context, particularly in the design of macrophage- and/or cytokine-depleting strategies.

Background/Objectives: The revolution for the treatment of melanoma came with the approval of checkpoint blockade antibodies. However, a substantial proportion of patients show primary or secondary resistance to this type of immunotherapy, indicating the need for alternative therapeutic strategies. Dendritic cells (DCs) of the skin are prime targets for vaccination approaches due to their potential to prime naïve T cells and their accessibility. This study aimed to develop and evaluate novel vaccines targeting the C-type lectin receptor DEC-205 to deliver melanoma-associated antigenic peptides to skin DCs. Methods: We cloned MHC-I-restricted peptides from the glycoprotein (gp)100_25–33 and Tyrosinase-related protein (trp)2_180–188 into the DEC-205 antibody sequence with modified peptide cutting sites from the OVA_257–264 SIINFEKL peptide. We tested their potential to induce CD8⁺ T cell responses in both in vitro and in vivo settings. Tumor growth inhibition was evaluated in the transplantable B16.OVA melanoma murine model using a multi-epitope DC-based vaccine combining both peptides. Results: The cross-presentation of both gp100 and trp2 peptides was confirmed in vivo when peptide sequences were flanked by the OVA_257–264 peptide cutting sites. Moreover, the combination of both antigenic peptides into a multi-epitope DC vaccine was required to inhibit B16.OVA melanoma growth. Conclusions: Our findings suggest that a DC-targeted vaccination approach using multiple epitopes deriving from melanoma antigens could represent a promising strategy for melanoma therapy.

Conventional dendritic cells (cDCs) are potent antigen-presenting cells (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity, and cancer. Here, we use fate mapping, functional analyses, and comparative cross-species transcriptomics to show that RORγt ⁺ DCs are a conserved, functionally versatile, and transcriptionally distinct type of DCs. RORγt ⁺ DCs entail various populations described in different contexts including Janus cells/RORγt-expressing extrathymic Aire-expressing cells (eTACs), subtypes of Thetis cells, RORγt ⁺ -DC (R-DC) like cells, cDC2C and ACY3 ⁺ DCs. We show that in response to inflammatory triggers, RORγt ⁺ DCs can migrate to lymph nodes and in the spleen can activate naïve CD4 ⁺ T cells. These findings expand the functional repertoire of RORγt ⁺ DCs beyond the known role of eTACs and Thetis cells in inducing T cell tolerance to self-antigens and intestinal microbes in mice. We further show that RORγt ⁺ DCs with proinflammatory features accumulate in autoimmune neuroinflammation in mice and men. Thus, our work establishes RORγt ⁺ DCs as immune sentinel cells that exhibit a broad functional spectrum ranging from inducing peripheral T cell tolerance to T cell activation depending on signals they integrate from their environment.

Since the success of solid organ transplants, such as human kidneys, livers and hearts, from the 50s to the 60s in the last century, the field of organ transplantation has progressed rapidly. Mainly due to modifications in surgical operation techniques and improvements in immunosuppressive therapy regimes, organ survival time can now be greatly prolonged. This progress has also been dependent upon the availability of appropriate animal models for organ transplantation. Therefore, the mouse heart transplantation model has developed into an irreplaceable research model for solid organ transplantation, providing indelible contributions to the field. In this review, we will provide an overview of the technical developments in murine heart transplantation, as well as its historical and current role for alloimmune research. Further, we will describe its current fields of application and its scientific achievements before we discuss potential future applications.