Although interleukin (IL)-6 is considered immunosuppressive and tumor-promoting, emerging evidence suggests that it may support antitumor immunity. While combining immune checkpoint inhibitors (ICIs) and radiotherapy in patients with pancreatic cancer (PC) has yielded promising clinical results, the addition of an anti-IL-6 receptor (IL-6R) antibody has failed to elicit clinical benefits. Notably, a robust TGFβ-specific immune response at baseline in PC patients treated solely with ICIs and radiotherapy correlated with improved survival. Recent preclinical studies demonstrated the efficacy of a TGFβ-based immune modulatory vaccine in controlling PC tumor growth, underscoring the important role of TGFβ-specific immunity in PC. Here, we explored the importance of IL-6 for TGFβ-specific immunity in PC. In a murine model of PC, coadministration of the TGFβ-based immune modulatory vaccine with an anti-IL-6R antibody rendered the vaccine ineffective. IL-6R blockade hampered the development of vaccine-induced T-cells and tumoral T-cell infiltration. Furthermore, it impaired the myeloid population, resulting in increased tumor-associated macrophage infiltration and an enhanced immunosuppressive phenotype. In PC patients, in contrast to those receiving only ICIs and radiotherapy, robust TGFβ-specific T-cell responses at baseline did not correlate with improved survival in patients receiving ICIs, radiotherapy and IL-6R blockade. Peripheral blood immunophenotyping revealed that IL-6R blockade altered the T-cell and monocytic compartments, which was consistent with the findings in the murine model. Our data suggest that the antitumor efficacy of TGFβ-specific T cells in PC depends on the presence of IL-6 within the tumor. Consequently, caution should be exercised when employing IL-6R blockade in patients receiving cancer immunotherapy.

We report long-term clinical and immunologic outcomes from the MM1636 trial (NCT03047928), which evaluated a peptide vaccine targeting IDO and PD-L1 in combination with nivolumab in patients with advanced melanoma. At a five-year follow-up, the combination demonstrated durable clinical efficacy, with a 25.5-month median progression-free survival. Serum proteomic profiling identified vaccine-specific immune signatures, with increase in CCL3, CCL4, and TNFα emerging as biomarkers of long progression-free survival. Increase in these markers were not observed in a matched anti-PD-1 monotherapy cohort, suggesting distinct immune modulation by the vaccine. Functional studies confirmed vaccine-induced targeting of myeloid cells and associated increase in these cytokines. These findings provide evidence for durable benefit from immune modulatory vaccination and nominate CCL3, CCL4, and TNFα as candidate biomarkers for response.

Transforming growth factor beta (TGFβ) plays a crucial role in pancreatic ductal adenocarcinoma (PDAC) progression by promoting immune suppression, fibrosis, and metastasis. Given its central role in shaping the tumor microenvironment, TGFβ has attracted significant clinical interest as a target for immunotherapy. One promising and innovative approach involves TGFβ-based immune-modulatory vaccines (IMVs). In this study, we explored the immunogenic potential of multiple TGFβ-derived epitopes and assessed the clinical relevance of TGFβ-specific T cells in PDAC patients. We identified T cell responses towards multiple epitopes, TGFβ‑15, TGFβ‑33, and TGFβ‑38, in both healthy donors and PDAC patients, with TGFβ‑33 eliciting particularly robust responses in the patient cohort. These primarily CD4⁺ T cells displayed proinflammatory, as well as notable cytotoxic, properties and recognized target cells in a TGFβ-dependent manner. Moreover, we found that higher baseline frequencies of TGFβ‑33-specific T cells correlated with improved clinical outcomes following combined immune checkpoint inhibitor therapy and radiotherapy. Interestingly, patients with baseline responses to multiple TGFβ-derived epitopes had longer overall and progression-free survival compared to those with responses to none or a single epitope. Using a single mRNA construct encoding multiple TGFβ epitopes, we demonstrated effective activation of T cells specific for distinct TGFβ epitopes. These findings support the potential of a multi-epitope TGFβ-derived immune-modulatory vaccine to enhance anti-tumor immunity, representing a promising strategy to improve therapeutic responses in PDAC.

Physically active individuals demonstrate enhanced immune competence. Efficient execution of effector function relies on chemokine receptor-regulated immune cell trafficking along chemokine gradients to sites of inflammation, infection, tumors, or tissue damage. This study investigates the impact of acute high-intensity interval training (HIIT) on chemokine receptor expression in leukocytes. Sixteen healthy participants completed a single HIIT session, and peripheral blood was collected before exercise (Bsl), immediately after (Ex02), and one hour later (Ex60). Surface expression of selected chemokine receptors was measured using flow cytometry on CD4⁺ T cells, γδ T cells, NK cells, and monocytes, followed by FlowSOM clustering. NK cells, CD4⁺ T cells, and γδ T cells were strongly mobilized at Ex02 and returned to or below baseline at Ex60. HIIT preferentially mobilized CX3CR1⁺ CXCR2⁺ CD56^dim NK cells, CD4⁺ T cells expressing CX3CR1^hi and CCR5⁺, and CX3CR1⁺ CD56⁺ γδ T cells, indicating mobilization of immune cells phenotypically associated with migratory and cytotoxic potential. Proportions of intermediate and non-classical monocytes increased at Ex02 and decreased at Ex60. In conclusion, HIIT induced a rapid redistribution of leukocyte subsets with chemokine receptor profiles suggesting enhanced endothelial interaction and migratory capacity toward effector tissues.