The biology of solid tumors is strongly determined by the interactions of cancer cells with their surrounding microenvironment. In this regard, pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) represents a paradigmatic example for the multitude of possible tumor–stroma interactions. PDAC has proven particularly refractory to novel immunotherapies, which is a fact that is mediated by a unique assemblage of various immune cells creating a strongly immunosuppressive environment in which this cancer type thrives. In this review, we outline currently available knowledge on the cross-talk between tumor cells and the cellular immune microenvironment, highlighting the physiological and pathological cellular interactions, as well as the resulting therapeutic approaches derived thereof. Hopefully a better understanding of the complex tumor–stroma interactions will one day lead to a significant advancement in patient care.

Significance: Increased tissue stiffness is a hallmark of several diseases such as organ fibrosis or cancer, and tissue fibroblasts play central roles in these pathologies. In tumors, stromal cells support the growth of cancer cells by supplying signaling molecules and nutrients, the latter also being provided by stromal autophagy. The mechanisms inducing these processes are, however, not well understood. Here, we demonstrate that an increased physical rigidity of a fibroblast’s environment is sufficient to evoke stromal autophagy. Mechanistically, matrix stiffness is transmitted via Integrin αV receptors and focal adhesion kinase, resulting in stabilization of AMPK at focal adhesion structures. Stiffness-mediated stromal autophagy supports the growth of neighboring tumor cells in vitro and in vivo, opening possibilities for anti-cancer therapies.

Intratumoral cytotoxic CD8+ T cells (CTL) enter a dysfunctional state characterized by expression of coinhibitory receptors, loss of effector function, and changes in the transcriptional landscape. Even though several regulators of T-cell exhaustion have been identified, the molecular mechanisms inducing T-cell exhaustion remain unclear. Here, we show that IL18 receptor (IL18R) signaling induces CD8+ T-cell exhaustion in a murine pancreatic cancer model. Adoptive transfer of Il18r−/− OT-1 CD8+ CTLs resulted in enhanced rejection of subcutaneous tumors expressing ovalbumin (OVA) as a model antigen (PancOVA), compared with wild-type OT-1 CTLs. Transferred intratumoral IL18R-deficient CTLs expressed higher levels of effector cytokines TNF and IFNγ and had reduced expression of coinhibitory receptors (PD-1, TIM-3, 2B4, LAG-3) and the transcription factors Eomes and TOX. Lower expression of coinhibitory receptors and TOX on IL18R-deficient versus IL18R-sufficient CD8+ T cells were confirmed in an orthotopic KPC model. IL18R-induced T-cell exhaustion was regulated by IL2/STAT5 and AKT/mTOR pathways, as demonstrated in an in vitro exhaustion assay. Concordantly, mice deficient in NLRP3, the molecular complex activating IL18, had decreased expression of coinhibitory receptors on intratumoral T cells and similar changes in signaling pathways at the transcriptome level. Thus, molecular pathways promoting T-cell exhaustion indicate an involvement of an NLRP3-expressing tumor microenvironment, which mediates IL18 release. The Cancer Genome Atlas analysis of patients with pancreatic carcinoma showed an association between NLRP3-mediated IL18 signaling and shorter survival. These findings indicate NLRP3-mediated IL18R signaling as a regulator of intratumoral T-cell exhaustion and a possible target for immunotherapy. Watch the interview with Veronika Lutz, PhD, and Christian Bauer, MD, corecipients of the 2025 Cancer Immunology Research Award for Outstanding Journal Article: https://vimeo.com/1100470935 See related Spotlight by Stromnes, p. 400

CD56⁺ T cells are a group of pro‐inflammatory CD3⁺ lymphocytes with characteristics of natural killer cells, being involved in antimicrobial immune defense. Here, we performed deep phenotypic profiling of CD3⁺CD56⁺ cells in peripheral blood of normal human donors and individuals sensitized to birch‐pollen or/and house dust mite by high‐dimensional mass cytometry combined with manual and computational data analysis. A co‐regulation between major conventional T‐cell subsets and their respective CD3⁺CD56⁺ cell counterparts appeared restricted to CD8⁺, MAIT, and TCRγδ⁺ T‐cell compartments. Interestingly, we find a co‐regulation of several CD3⁺CD56⁺ cell subsets in allergic but not in healthy individuals. Moreover, using FlowSOM, we distinguished a variety of CD56⁺ T‐cell phenotypes demonstrating a hitherto underestimated heterogeneity among these cells. The novel CD3⁺CD56⁺ subset description comprises phenotypes superimposed with naive, memory, type 1, 2, and 17 differentiation stages, in part represented by a phenotypical continuum. Frequencies of two out of 19 CD3⁺CD56⁺ FlowSOM clusters were significantly diminished in allergic individuals, demonstrating less frequent presence of cells with cytolytic, presumably protective, capacity in these donors consistent with defective expansion or their recruitment to the affected tissue. Our results contribute to defining specific cell populations to be targeted during therapy for allergic conditions.

Purpose: To describe the perfusion patterns of peripheral organizing pneumonia (POP) by contrast-enhanced ultrasound (CEUS) and their correlation with vascularization patterns (VPs) represented by immunohistochemical CD34 endothelial staining. Methods: From October 2006 until December 2020, 38 consecutive patients with histologically confirmed POPs were standardized-examined by CEUS. The time to enhancement (TE; classified as an early pulmonary-arterial [PA] pattern of enhancement vs. delayed bronchial-arterial [BA] pattern of enhancement), the extent of enhancement (EE; classified as marked or reduced), the homogeneity of enhancement (HE; classified as homogeneous or inhomogeneous), and the decrease of enhancement (DE; classified as rapid washout [<120s] or late washout [≥120s]) were evaluated retrospectively. Furthermore, tissue samples from the study patients were immunohistochemically stained with CD34 antibody. The presence of avascular areas (AAs) and the VPs were evaluated in all tissue samples. Results: The majority of POPs showed a BA pattern of enhancement (71.1%), an isoechoic marked enhancement (76.3%), and an inhomogeneous enhancement (81.6%). A rapid DE was observed in 50.0% of cases. On CD34 staining, all POPs had a chaotic VP, indicating BA neoangiogenesis. AAs (abscess, necrosis, hemorrhage) were identified in (41.9%) cases with an inhomogeneous enhancement on CEUS. Conclusion: On CEUS, POPs predominantly revealed a marked inhomogeneous BA pattern of enhancement with a rapid washout in 50% of cases. Furthermore, we demonstrated that the presence of a PA pattern of enhancement, found in 28.9% of POPs, did not exclude a BA neoangiogenesis as an important feature of chronic inflammatory and malignant processes.

Neuroendocrine tumors of the small intestine (SI‐NETs) often develop lymph node metastasis (LNM)‐induced mesenteric fibrosis (MF). MF can cause intestinal obstruction as well as ischemia and render surgical resection technically challenging. The underlying pathomechanisms of MF are still not well understood. We examined mesenteric LNM and the surrounding stroma compartment from 24 SI‐NET patients, including 11 with in situ presentation of strong MF (MF+) and 13 without MF (MF−). Differential gene expression was assessed with the HTG EdgeSeq Oncology Biomarker Panel comparing MF+ with MF− within LNM and paired stromal samples, respectively. Most interesting differentially expressed genes were validated by reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) in combination with validation of associated protein levels utilizing immunohistochemistry (IHC) staining of MF+ and MF– formalin‐fixed, paraffin‐embedded (FFPE) patient samples. Overall, 14 genes measured with a 2549‐gene expression panel were differentially expressed in MF+ patients compared to MF−. Of those, nine were differentially expressed genes in LNM and five genes in the stromal tissue (>2‐fold change, p < .05). The top hits included increased COMP and COL11A1 expression in the stroma of MF+ patients compared to MF−, as well as decreased HMGA2, COL6A6, and SLC22A3 expression in LNM of MF+ patients compared to LNM of MF− patients. RT‐qPCR confirmed high levels of COMP and COL11A1 in stroma samples of MF+ compared to MF− patients. IHC staining confirmed the enrichment of α‐smooth muscle actin‐positive fibrosis in MF+ compared to MF− patients with corresponding increase of COMP‐expressing stromal cells in MF+. Since COMP is associated with the known driver for fibrosis development transforming growth factor beta and with a cancer‐associated fibroblasts enriched environment, it seems to be a promising new target for MF research.