Prognostic relevance of tertiary lymphoid organs following neoadjuvant chemoradiotherapy in pancreatic ductal adenocarcinoma

Abstract

The efficacy of preoperative neoadjuvant chemoradiotherapy ( NAC ) in cases of pancreatic cancer with extremely poor prognoses has been reported. In this study, we aimed to identify novel biomarkers that reflect prognoses following chemoradiotherapy using tertiary lymphoid organs ( TLO ) expressed in the tumor microenvironment. Resected tumor specimens were obtained from 140 pancreatic cancer patients. We retrospectively investigated the clinical relevance of TLO by categorizing patients into those who underwent upfront surgery (surgery first [ SF ]) and those who received NAC. The immunological elements within TLO were analyzed by immunohistochemistry ( IHC ). In the IHC analysis, the proportions of CD 8+ T lymphocytes, PNA d+ high endothelial venules, CD 163+ macrophages and Ki‐67+ cells within the TLO were higher in the NAC group than in the SF group. In contrast, the proportion of programmed cell death‐1+ immunosuppressive lymphocytes within TLO was lower in the NAC group than in the SF group. The NAC group demonstrated favorable prognoses compared with the SF group. In the multivariate analysis, the TLO /tumor ratio was determined as an independent predictive prognostic factor. In conclusion, the administration of preoperative chemoradiotherapy may influence the immunological elements in the tumor microenvironment and result in favorable prognoses in pancreatic ductal adenocarcinoma patients.

Tertiary Lymphoid Structures and B cells: Clinical impact and therapeutic modulation in cancer

“…It was later found that the density of B cells follicles present in TLS were also associated with PFS and OS [29]. These findings have been extended to a large array of cancers and a favorable prognostic impact has been reported in SCLC [12], BC [39,40,44], CRC [11,43], GIST [38], HCC [34,35], melanoma [15,16,42], pancreatic cancers [45,46,52], oral squamous [37] and ovarian cancer [30,36] (Table 1). After neoadjuvant chemotherapy, a similar TLS pattern was found that the one found in chemotherapy-naive patients, with comparable densities of tumor-infiltrating CD8 + and DC-LAMP + cells, a similar spatial organization and a favorable association with outcome in NSCLC [53].…”

“…The proposed mechanism of action is that chemotherapy, by increasing antigen release from dying tumor cells and promoting inflammation, provokes the activation of the complement component C3 which activates the Complement Receptor 2 (CR2) bearing B cells to express ICOSL, resulting in activation of Th1 and cytotoxic T cells [95]. The proportions of TLS were also found to be higher and predictive of response in group of patients with pancreatic cancer treated by neoadjuvant therapy than in those treated by surgery first [52]. In Hepatoblastoma (HB) pathological reviewing identified Ipilimumab, an anti-CTLA-4 antibody, combined with a demethylating agent which favors tumor cell immunogenicity, highly increased the B cell infiltrate in melanoma tumors [98].…”

B cells and cancer: To B or not to B?

“…TLSs are ectopic lymphoid organs that develop in inflamed tissues in the context of chronic antigen stimulation. In cancers, proimmunogenic inflammation can also be induced or increased by treatments such as chemotherapy ( Lu et al, 2020 ; Kuwabara et al, 2019 ) or radiotherapy ( Boivin et al, 2018 ). TLSs are formed in inflamed sites, starting upon contact of IL-7–secreting stromal cells with tissue-resident monocytic cells, Th17 cells, or B cells in a CXCL13-rich milieu ( Buckley et al, 2015 ; Nayar et al, 2016 ; Barone et al, 2016 ; Jones et al, 2016 ).…”

Tertiary Lymphoid Structures in Cancer: The Double-Edged Sword Role in Antitumor Immunity and Potential Therapeutic Induction Strategies

“…This may involve so-called immunogenic cell death, a controlled cell death process that produces damage-associated molecular patterns that can be used as adjuvants to initiate an immune response through the recruitment and activation of DCs ( 162 ). Administration of preoperative chemoradiotherapy (neoadjuvant chemotherapy, NAC) was associated with increased TLS formation and may affect the immunological composition of the TME and confer a favorable prognosis in patients with pancreatic ductal adenocarcinoma ( 163 ). However, corticosteroid therapy during chemotherapy impaired GC formation and reduced TLS prognostic value in patients with lung cancer ( 164 ).…”