Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS+ patients displayed significantly higher plasma cell frequencies compared to TLS- patients in the PR group. Additionally, high densities of CD20+ intratumoral B cells were significantly associated with longer overall survival in the PR group. While CD20+ B cells held no prognostic value for NeoTx patients, an increased frequency of proliferating CD20+Ki67+ B cells emerged as an independent prognostic factor for longer survival in the NeoTx group. These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients.

Carcinoid syndrome caused by a pulmonary carcinoid mimics intestinal manifestations of ulcerative colitis: A case report.

BACKGROUND: Pulmonary carcinoids are rare, low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior. Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi. Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5% of patients with neuroendocrine tumors. Due to such nonspecific presentation, most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. CASE SUMMARY: We report the case of a 48-year-old male who presented with cough, dyspnea, a history of recurrent pneumonitis, and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid. CONCLUSION: We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.

Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion.

Solid cancers like pancreatic ductal adenocarcinoma (PDAC), a type of pancreatic cancer, frequently exploit nerves for rapid dissemination. This neural invasion (NI) is an independent prognostic factor in PDAC, but insufficiently modeled in genetically engineered mouse models (GEMM) of PDAC. Here, we systematically screened for human-like NI in Europe's largest repository of GEMM of PDAC, comprising 295 different genotypes. This phenotype screen uncovered 2 GEMMs of PDAC with human-like NI, which are both characterized by pancreas-specific overexpression of transforming growth factor α (TGF-α) and conditional depletion of p53. Mechanistically, cancer-cell-derived TGF-α upregulated CCL2 secretion from sensory neurons, which induced hyperphosphorylation of the cytoskeletal protein paxillin via CCR4 on cancer cells. This activated the cancer migration machinery and filopodia formation toward neurons. Disrupting CCR4 or paxillin activity limited NI and dampened tumor size and tumor innervation. In human PDAC, phospho-paxillin and TGF-α-expression constituted strong prognostic factors. Therefore, we believe that the TGF-α-CCL2-CCR4-p-paxillin axis is a clinically actionable target for constraining NI and tumor progression in PDAC.

Clinically Actionable Strategies for Studying Neural Influences in Cancer.

Neuro-glial activation is a recently identified hallmark of growing cancers. Targeting tumor hyperinnervation in preclinical and small clinical trials has yielded promising antitumor effects, highlighting the need of systematic analysis of neural influences in cancer (NIC). Here, we outline the strategies translating these findings from bench to the clinic.

The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma - A systematic review and meta-analysis.

OBJECTIVES: To assess the impact of neural invasion/NI on overall survival/OS and tumor recurrence in pancreatic ductal adenocarcinoma/PDAC. SUMMARY BACKGROUND DATA: NI is a histopathological hallmark of PDAC. Although some studies suggested an important role for NI on OS, disease-free/DFS and progression-free survival/PFS in PDAC, there is still no consensus on the actual role of NI on survival and local recurrence in PDAC. METHODS: Pubmed, Cochrane library, Ovid and Google Scholar were screened for the terms "pancreatic ductal adenocarcinoma", "pancreatic cancer", "survival", "tumor recurrence" and "perineural invasion". The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used for systematic review and meta-analysis. Articles meeting predefined criteria were critically analysed on relevance, and meta-analyses were performed by pooling univariate and multivariate hazard ratios/HR. RESULTS: A total number of 25 studies on the influence of NI on tumor recurrence, and 121 studies analysing the influence of NI on survival were identified by systematic review. The HR of the univariate (HR 1.88; 95%-CI 1.71-2.07; p < 0.00001) and multivariate meta-analysis (HR 1.68; 95%-CI 1.47-1.92; p < 0.00001) showed a major impact of NI on OS. Likewise, NI was associated with decreased DFS (HR 2.53; 95%-CI: 1.67-3.83; p = 0.0001) and PFS (HR 2.41; 95%-CI: 1.73-3.37: p < 0.00001) multivariate meta-analysis. CONCLUSIONS: Although the power of this study is limited by missing pathological procedures to assess the true incidence of NI, NI appears to be an independent prognostic factor for OS, DFS and PFS in PDAC. Therefore, NI should be increasingly considered in patient stratification and in the development of novel therapeutic algorithms.

The impact of neoadjuvant therapy on the histopathological features of pancreatic ductal adenocarcinoma - A systematic review and meta-analysis.

BACKGROUND: Due to increased rates of curative tumor resections exceeding 60% after FOLFIRINOX-treatment, neoadjuvant therapy/NTx is increasingly recognized as an effective therapy option for downstaging borderline or locally advanced pancreatic ductal adenocarcinoma/PDAC. Yet, the effects of NTx on the common histopathological features of PDAC have not been systematically analysed. Therefore, the aim of the current study was to assess the impact of NTx on relevant histopathological features of PDAC. PATIENTS AND METHODS: Biomedical databases were systematically screened for predefined searching terms related to NTx and PDAC. The Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were used to perform a systematic review and meta-analysis. Articles meeting the predefined criteria were analysed on relevance, and a meta-analysis was performed. RESULTS: A total of 9031 studies could be identified that analysed the effect of NTx on PDAC. Only 35 studies presented comparative data on the histological features of neoadjuvantly treated vs. upfront resected PDAC patients. In meta-analyses, the beneficial effect of NTx was reflected by reduced tumor size (T1/2: RR 2.87, 95%-CI: 1.52-5.42, P=0.001, T3/4: RR 0.78, 95%-CI: 0.69-0.89, P=0.0002), lower N-Stage (N0: RR 2.14, 95%-CI: 1.85-2.46, P<0.00001, N1: RR 0.59, 95%-CI: 0.53-0.65, P<0.00001), higher R0-rates (R0: RR 1.13, 95%-CI: 1.08-1.18, P<0.00001, R1: RR 0.66, 95%-CI: 0.58-0.76, P<0.00001), less perineural invasion (Pn1: RR 0.78, 95%-CI: 0.73-0.83, P<0.00001), less lymphatic vessel invasion (RR: 0.50, 95%-CI: 0.36-0.70, P<0.0001) and fewer G3-tumors (RR 0.82, 95%-CI: 0.71-0.94, P=0.005). CONCLUSIONS: NTx in PDAC seems to exert its beneficial effect in borderline or locally advanced PDAC over genuine tumor downstaging. Thus, although at least 40% of all NTx treated patients remain unresectable even with modern NTx regimes, neoadjuvantly treated PDAC showed not only increasing resectability rates especially after FOLFIRINOX, but even reach a lower tumor stage than primarily resected PDAC.

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells.

Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.