Perineural Invasion and TAMs in Pancreatic Ductal Adenocarcinomas: Review of the Original Pathology Reports Using Immunohistochemical Enhancement and Relationships with Clinicopathological Features

Abstract

Objectives: Tumor-associated macrophages (TAMs) are thought to be involved in the perineural invasion (PNI) process and to be associated with poor prognoses. The associations between TAMs, PNI, and clinicopathological features in pancreatic ductal adenocarcinomas (PDAs) remain to be elucidated. Methods: Fifty-nine PDA patients who had undergone pancreaticoduodenectomy were retrospectively examined. The PNI statuses and TAMs were reviewed following H&E staining and S-100, CD68, and CD163 immunohistochemical staining. The relationships between PNI, TAMs, and overall survival and various clinical and histopathologic factors were investigated. Results: PNI was identified in 83% (49/59) of the cases, the TAM density of the PNI+ group was greater than that of the PNI- group, and the infiltrating TAMs around the nerves that were invaded by cancer were much more numerous than those around the nerves without cancer cell invasion. The incidences of PNI, lymph node metastasis, high serum CA19-9 level, cancers in the body/tail, and advanced pathological stage were associated with shorter OSs. In the PNI+ group, lymph node metastasis and high levels of TAM infiltration were associated with worse prognoses. Conclusions: TAMs might enhance PNI, and the incidence of PNI was associated with poor prognosis. PNI+ status and high levels of TAM infiltration further worsen the prognosis. Therapies targeting TAMs might represent auxiliary and preventive treatment for PNI in PDA patients.

Inflammatory Monocytes Promote Perineural Invasion via CCL2-Mediated Recruitment and Cathepsin B Expression

“…We analyzed clinical outcomes in our PDA cohort (Supplementary Table 2) and observed a significantly higher proportion of PNI foci infiltrated by macrophages in patients who developed a local recurrence (Supplementary Fig. S12), a finding that supports prior work showing an adverse clinical impact of macrophage infiltration around nerves in PDA (5). To determine if macrophage-produced CTSB is relevant in promoting PNI by PDA in patients, we co-stained human PDA samples with anti-CD68 and anti-cathepsin B.…”

“…Modern theories of PNI pathogenesis have placed significant focus on the role of the nerve microenvironment with PNI resulting from well-orchestrated interactions between cancer and the nerve (2, 3). While the cellular components of the nerve microenvironment are relatively static and well defined under homeostasis, PNI develops within a dynamic and complex tumor microenvironment that is enriched with immune cells recruited from the circulation (4, 5) and whose contribution to nerve invasion is unclear. Our knowledge gap in this area stems in part from the inability of in vitro PNI models to recapitulate the immune milieu, and the lack of consistent and quantifiable nerve invasion with current in vivo tumor models (6).…”

“…Endoneurial macrophages represent a subset of tissue-resident macrophages that inhabit normal peripheral nerves, which are distinct from the hematogenous macrophages that are derived from monocytes recruited under various pathological conditions (11). In tumors with a strong predilection for PNI such as pancreatic ductal adenocarcinoma (PDA) (1), the microenvironment is enriched with monocytes and macrophages from the circulation, which contribute to PDA tumorigenesis (12) and negatively mediate disease progression and local invasion (4, 5). While there is strong evidence that recruited inflammatory monocytes (IM) may promote distant metastases (13, 14), the potential contribution of recruited IM towards the progression of cancer along nerves is unclear.…”

“…We hypothesized that this conserved monocyte response to nerve injury may be induced by invading cancer cells to inadvertently promote PNI. Macrophages are detected in regions of PNI by PDA and their presence is associated with poor clinical outcome (5, 6, 10, 18). However, despite appreciation of their clinical relevance, we currently have a limited understanding of their origin, recruitment mechanism, and function within nerves.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Up to date, this task has been accomplished using CD11c or NOS2 for M1 TAMs, and CD163, CD204, or CD206 for M2 TAMs. Indeed, increased M1 TAM densities seem to be associated with a favorable clinical outcome in NSCLC (Ma et al, 2010;Ohri et al, 2009), ovarian , colorectal (Edin et al, 2012), and gastric cancer (Zhang, Wang, et al, 2014a), while those of M2 are linked to poor prognosis in several tumors, including NSCLC (Hirayama et al, 2012;Ohtaki et al, 2010;Zeni et al, 2007), mesothelioma (Cornelissen et al, 2014), esophageal (Shigeoka et al, 2013), gastric cancer (Kawahara et al, 2010;Pantano et al, 2013), pancreatic (Hou et al, 2014;Ino et al, 2013;Kurahara et al, 2011;Sugimoto et al, 2014;Sugimura et al, 2015;Zeng et al, 2014), CRC (Herrera et al, 2013), HCC (Kong et al, 2013), Hodgkin lymphoma , renal (Dannenmann et al, 2013;Komohara et al, 2011;Xu et al, 2014), urothelial (Ichimura et al, 2014), breast (Medrek et al, 2012), endometrial (Kübler et al, 2014), ovarian (Lan et al, 2013), melanoma ( Jensen et al, 2009), and squamous oral carcinoma . Additionally, some studies have demonstrated that, when associated with poor clinical outcome, CD68 + cells are often correlated with the tumor microvessel density, in addition to HIF, VEGF (Chai et al, 2008), and matrix metalloproteinase expression (Bolat et al, 2006;Hanada et al, 2000;Leek et al, 1996;Osinsky et al, 2011;Valković et al, 2002), suggesting that they might have an ...…”