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.