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Diab et al. J Cancer Metastasis Treat 2022;8:42 https://dx.doi.org/10.20517/2394-4722.2022.60 Page 9 of 14

CAFs, and they show high expression of genes involved in fibroblast activation and proliferation, including
the collagen genes COL1A1 and COL1A2, insulin-like growth factor-1 (IGF-1), and lysyl oxidase homolog 2
[80]
[81]
(LOXL2) . A high density of B cells in TLT is associated with improved survival . Interestingly, in a
mouse model devoid of TLT, depletion of B cells using an anti-CD20 antibody restored anti-tumor
immunity . Therefore, the prognostic relevance and anti-tumor potential of B cells rely on their spatial
[80]
[80]
organization within PDAC . The spatial localization of T and B lymphocytes within TLT is crucial for the
recruitment of tumor-infiltrating T cells . B cells appear to be regulated by follicular helper T cells .
[80]
[80]
Interestingly, depletion of B cells may prevent the formation of TLT, which might be detrimental in PDAC
as the tumors are deprived of effector cell localization and anti-tumor immune response .
[78]
A subset of regulatory B cells, also referred to as B1 regs, produce IL35, which promotes tumor progression
and cytotoxic T cell evasion . Bregs express high levels of PD-L1 which interacts with PD-1 on cytotoxic T
[78]
cells, rendering them exhausted [82,83] . Through the activity of Bruton tyrosine kinase (BTK), B cells interact
with TAMs and reprogram them to the pro-tumoral M2 phenotype . In studies with Ink4 2.2 and p53 2.1.1
[84]
mouse cell lines and male FVB/n mice, inhibition of BTK with ibrutinib resulted in the reprogramming of
TAMs to the anti-tumoral M1 phenotype, increased cytotoxic T cell infiltration, and decreased tumor
growth . This provided the basis of the RESOLVE trial, in which treatment-naïve metastatic PDAC
[84]
patients were randomized to ibrutinib or placebo, combined with chemotherapy . Unfortunately, the
[85]
combination failed to show a survival benefit . This underscores that there are likely more intricate cross-
[85]
[86]
talks between tumor and stromal cells and that targeting one signaling pathway is not sufficient .
Additionally, caution must be exercised when deducing results from preclinical models, as they might not
accurately mimic human cancer . One example is that orthotopic models lack TLT .
[80]
[86]
As mentioned above, CD40, a member of the tumor necrosis factor receptor superfamily, activates antigen-
presenting cells, such as dendritic cells and B cells [57,87] . In studies on Panc02 mouse pancreatic cancer cell
lines and C57BL/6 (H-2b) mice, treatment with CD40 agonistic antibody resulted in T-cell-dependent
tumor regression and improved survival . Synergy was observed with PD-1 blockade on similar models .
[46]
[88]
A phase 1 trial evaluated the safety of the CD40 agonist APX005M (sotigalimab) in combination with
chemotherapy, with or without nivolumab in treatment-naïve metastatic PDAC patients . The
[57]
combination was safe and associated with a promising efficacy signal . Other CD40 agonists are currently
[57]
[89]
being tested in earlier stages of PDAC .
Dendritic cells and other populations
Over the last decade, dendritic cells (DCs) have gained popularity as a subject of interest in the field of
PDAC, especially in the development of cancer vaccines . DCs represent a diverse group of antigen-
[90]
[91]
presenting cells that are able to recognize tumor antigens and generate tumor-specific immunity . The
presence of DCs is associated with longer survival in PDAC, both in the metastatic and early stages [92,93] .
They are also associated with a greater infiltration of cytotoxic T cells . However, DCs are a rare
[94]
population in PDAC, have an attenuated function, and are localized to the periphery of the tumor, all of
which inhibit their anti-tumor effects . Several trials are capitalizing on DCs as a therapeutic target,
[95]
including the use of CD40 agonisms mentioned above [96-98] .

Other components of innate and adaptive immunity, including natural killer cells, γδ T cells, and other
innate lymphoid cells (ILCs), have recently gained attention; however, their roles continue to be
incompletely understood. A key component of innate immunity, natural killer cells (NK cells) in PDAC also
have an attenuated anti-tumor function, tend to reside in the periphery of the tumor, and are associated
with improved survival [99,100] . γδ T cells are a more abundant type of lymphocyte with pro-tumoral activity