5.2: Prognostic value after PC immunotherapy

Pancreatic cancer is notorious for its poverty in prognosis, and in recent years, there has been a lot of researches on TANs for the prognosis of pancreas cancer. The ratio of neutrophils to lymphocytes (NLR), which is regarded as one of the indicators of the systemic inflammatory response caused by PC cells, facilitating the infiltration of neutrophils and lymphocytes, is a useful predictor of PC prognosis following surgery[135, 136]. The relationship between NLR and the phenotypes of immune cells in patients with PDAC is closely connected. Patients with NLR ≤ 2.5 exhibited a notable rise in the CD3+ and CD8+/CD28+ T cell subsets, whereas a significant decline was observed in the CD8+/CD28- and CD4+/CD25+ cell subsets[135]. Based on these, the NLR also having prognostic value for PC immunotherapy is not unexpected. After undergoing radiotherapy, the NLR can serve as a predictive indicator for pancreatic cancer patients who are treated with anti-PD-1 antibodies and stereo-directed radiotherapy[137]. Patients with PDAC who experience a substantial alteration in NLR following two doses of immune checkpoint blockade are at an increased likelihood of mortality[138]. Furthermore, the outcome in patients with PDAC treated with PD-1 inhibitors is associated with the combined indicators of NLR and LADH[139]. However, NLR, which predicts PC immunotherapy results, has not obtained a recognized critical value currently. Many research results are different and there are problems with less research samples. Additionally, N1/N2 is likely to be a future prediction target[140].

6. The future of PC immunotherapy based on TANs

Increasing evidence links the TANs to the immunosuppressive microenvironment of PC. TANs, as a novel area of study, have significant potential for PC immunotherapy.  However, PC immunotherapy often leads to immune-related adverse events (irAEs) such as skin inflammation, inflammation of the thyroid gland, lung inflammation, inflammation of the colon, liver inflammation, kidney inflammation, inflammation of the pituitary gland, inflammation of the adrenal glands, and muscle inflammation[141]. IrAEs are believed to occur due to a disruption in self-tolerance, which is influenced by T-cell responses specific to antigens, autoantibodies, B cells, and cytokines. Interestingly, neutropenia is a common occurrence in almost all immunotherapies, warranting investigation into whether TANs play a role in the mechanisms underlying these adverse events and whether targeting TANs can mitigate them.  Additionally, recent research has highlighted the importance of the interaction between TANs and the microbiota[142]. Modulating the microbiome has been shown to enhance the anti-cancer immune response and facilitate successful PC immunotherapy[143]. Given these findings, it is worth exploring the potential for targeting TANs and their interaction with the microbiota in PC immunotherapy. Hence, exploring the impact of focusing on TANs in medical immunotherapy for PC shows great potential, yet additional investigation is necessary to accelerate its clinical application. These researches would offer valuable direction for the management of medication, specifically concentrating on the subsequent encouraging domains.
1) An encouraging strategy for utilizing TANs in the treatment of PC involves employing neutrophils in nanomedicine applications. Nanomedicine is an effective means of targeted tumor treatment. Neutrophils have become a viable option for drug transportation[144] and the utilization of neutrophilic membrane-derived nanocouples for delivering medication [145] is anticipated for clinical use in the near future. Nanoparticles (NPs) have the ability to selectively target activated neutrophils, potentially utilizing them for drug delivery[146]. Moreover, it is crucial to take into account that therapies on personal computers like radiation treatment and immunizations can inherently trigger the migration and infiltration of neutrophils, which can be advantageous for the implementation of this method. However, PC chemotherapy with drugs like gemcitabine and immunotherapy such as CAR-T cell therapy may result in neutrophils deficiency, posing challenges for the implementation of this technique.
2) For immunotherapy of PC, perhaps TANs are expected to become the main force in the future, and we will place our hope on chimeric antigen receptor neutrophils (CAR- neutrophils). Yun Chang’s group utilizes CRISPR/Cas9 to modify human pluripotent stem cells, introducing different anti-Glioblastoma CAR constructs that contain either T-specific CD3ζ or neutrophil-specific γ-signaling domains. CAR-neutrophils are produced by selecting the CAR constructs that yield the most efficient anti-cancer effects. The main goal is to deliver nanodrugs that respond to the tumor microenvironment in order to target Glioblastoma, while avoiding any extra inflammation at the tumor locations[147, 148]. The non-specific and non-invasive nature of this method makes it an attractive option for treating pancreatic tumors. Therefore, TANs, specifically CAR- neutrophils, are expected to have a crucial part in the forthcoming immunotherapy of PC.
3) The combination of multi-immunotherapy is anticipated to be the key to the future of PC treatment, with TANs playing a crucial role as effective aides. Through iNOS-dependent mechanisms, Daniel Hirschhorn’s team showcased the ability of TANs to eliminate tumor antigens with evasive mutations, thereby exerting anti-tumor effects. The results of this study have important consequences for the use of CD4+ T cell treatment, especially when combined with co-stimulated therapy that includes OX40 or CTLA-4 blockade[149]. Notably, this approach shows promise in eradicating tumors hat harbor antigen escape variants. Therefore, the role of TANs in mediating the anti-tumor function offers valuable insights into the future directions of PC immunotherapy treatment.