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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 7 of 14

CD40, a member of the TNF receptor superfamily, is expressed broadly on immune cells, including
[54]
monocytes and macrophages . In KPC mouse models, treatment with the CD40 agonist FGK45 resulted in
upregulation of MHC II in macrophages from the tumor and spleen, suggesting that CD40 activation
[54]
reprograms TAMs to their anti-tumor phenotype . Combining CD40 agonism with chemotherapy
resulted in increased T cell infiltration, decreased tumor burden, and increased susceptibility to immune
checkpoint therapy [54-56] . In a phase 1 trial with treatment-naïve metastatic PDAC patients, the combination
of the CD40 agonist APX005M (sotigalimab) with chemotherapy was associated with a promising response
[57]
rate of 58% .
In addition to the many functions in PDAC, myeloid cells play a role in establishing a pre-metastatic niche
[58]
and promoting metastatic disease . This is carried out either by 1- the physical translocation of myeloid
cells to organs outside of the pancreas and direct cross-talks with host organs or by 2- tumor-derived
exosomes which can carry out these changes more distally . A body of evidence now shows that MDSCs
[29]
[58]
colonize distal organs prior to tumor cells . Granulin secreted from macrophages recruited to the liver
activates myCAFs and creates a permissible environment for tumor growth and survival . Lastly,
[59]
upregulated STAT3 in hepatocytes recruits myeloid cells to the liver by secreted serum amyloid A1 and A2,
leading to liver fibrosis . This results in increased susceptibility of the liver to tumor seeding and
[58]
growth . Ablation of the IL6/STAT3/serum amyloid A pathway resulted in fewer recruited MDSCs which
[58]
[58]
translated to the prevention of metastatic dissemination .
LYMPHOCYTES
T cells
The T cell population in PDAC TME encompasses different subpopulations with distinguished spatial
distributions and roles that can be immune stimulating or suppressive, the former of which is largely
restrained by tumor cells and the other constituents of the TME [Figure 3]. Cytotoxic or effector CD8 T
+
cells represent a small subset and are confined to the tumor periphery . A high cytotoxic T cell infiltration
[60]
of tumors is associated with improved survival . A growing body of literature shows that cytotoxic T cells
[60]
strongly express immune checkpoint markers, such as PD-1, VISTA, and TIGIT, and are exposed to their
ligands expressed on immune suppressive stromal cells, which make them susceptible to inhibition by
different mechanisms [61-63] . Additionally, cytotoxic T cells are the subject of immunosuppressive cytokines
produced by tumor and stromal cells, such as IL-6, TGFβ1, CXCL12, and IL-10 [61-63] . Cytotoxic T cell
function is further inhibited by the relative scarcity of antigen-presenting cells within the TME and
insufficient tumor antigenicity [60,64] . Lastly, the dense stroma surrounding tumors acts as a physical barrier
for the recruitment of cytotoxic T cells [16,65] . An abundant component of the extracellular matrix is fibrillar
collagens, such as type I and III collagen [16,65] . The major producer of fibrillar collagens are CAFs, and tumor
[66]
cells produce a small amount of CAFs .

Initiatives to enhance the activity of cytotoxic T cells are ongoing . This includes a phase I/II trial that is
[67]
being conducted by our group (NCT04191421) . In this trial, patients with metastatic, treatment-refractory
[67]
disease receive spartalizumab, a checkpoint inhibitor of PD-1, and siltuximab, which inhibits IL-6, in an
attempt to sensitize these tumors to PD-1 blockade .
[67]
Studies on human as well as mouse models (KPC and others) showed that blockade of the CXCR4/CXCL12
pathway resulted in increased T cell infiltration and synergized with immune checkpoint inhibitors [68-70] .
Combining the CXCR4 blocker BL-8040 (motixafortide) with chemo- and immunotherapy showed a
promising signal in patients with metastatic PDAC in the phase II trial COMBAT .
[68]