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Page 4 of 14 Diab et al. J Cancer Metastasis Treat 2022;8:42 https://dx.doi.org/10.20517/2394-4722.2022.60

synthesis of hyaluronan, which is a major component of the ECM regarded as a significant barrier to the
[20]
treatment of PDAC . Efforts targeting hyaluronan in PDAC include the use of pegylated hyaluronidase in
combination with chemotherapy [27,28] . Although early results were promising, later-phase trials showed no
survival benefit [27,28] .

Antigen-presenting CAFS
Like iCAFs, antigen-presenting CAFs (apCAFs), also reside in the periphery of tumor in areas of extensive
desmoplasia and are likely regulated by interferon gamma (IFNγ) signaling . apCAFs express genes that
[20]
belong to the major histocompatibility complex (MHC) class II family, such as histocompatibility 2, class II
antigen A, alpha (H2-Aa) and beta 1 (H2-Ab1), that encode the alpha and beta chains of MHC class II, and
[20]
CD74 that encodes the invariant chain . Additionally, they express unique markers such as Serum
Amyloid A3, which is regarded as a pro-tumorigenic factor in pancreatic CAFs, and Secretory Leukocyte
Peptidase Inhibitor, which was previously identified as a pro-inflammatory gene in dysplastic skin
fibroblasts . Pathways upregulated in apCAFs include those involved in antigen presentation and
[20]
processing, fatty acid metabolism, MYC and MTORC1 signaling . Proteins upregulated in apCAfs include
[20]
other regulators of immune activity such as Bcam (CD239) and F11r (CD321), members of the
immunoglobulin superfamily, and interferon regulatory factor 5, which is an Interferon-regulating
[20]
protein . apCAFs exhibit a higher activity for Stat1, which is known to mediate MHCII expression in
response to IFNγ . apCAFs have the capacity to present a model antigen to CD4+ T cells, but they lack the
[20]
costimulatory molecules needed to induce T cell proliferation. Therefore, it is likely that the MHC class II
expressed by apCAFs serves as a decoy receptor to deactivate CD4+ T cells by inducing either anergy or
differentiation into regulatory T cells (Tregs), and in that, contributes to an immune suppressive TME .
[20]

MYELOID CELLS
[29]
One of the abundant immune cells that play a crucial role in the progression of PDAC is myeloid cells . Of
those, myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are some of
[29]
the most studied types . Although with similar phenotypes and surface markers, MDSCs and TAMs are
[29]
two distinct populations [Figure 2] . Sophisticated cross-talk between these cells and tumor cells
collectively leads to resistance to chemotherapy, inhibition of effector T cell, and promotion of tumor
invasiveness and metastases.

MDSCs
[30]
MDSCs are characterized by an immature, immune suppressive phenotype . MDSCs are classified into
two subsets: 1- polymorphonuclear-MDSC (PMN-MDSC) that share markers expressed on neutrophils,
and 2- monocytic-MDSC (M-MDSC) that share markers expressed on monocytes and macrophages [6,29] . A
third subpopulation of MDSCs exists, representing a common progenitor of MDSCs, referred to as early-
stage MDSC or eMDSC [29,31,32] . This subpopulation has yet to be functionally evaluated in PDAC . MDSCs
[29]
in PDAC are bone marrow-derived, and their formation is driven by kras, tumor-derived granulocyte-
macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and
[30]
macrophage colony-stimulating factor (M-CSF) . Although PMN-MDSCs are more abundant than M-
MDSCs, M-MDSCs are more immune suppressive [30,33] . Phenotypic differences between murine and human
MDSCs exist [31,32] . For example, murine MDSCs were originally described as CD11b and Gr-1 +[31,32] . Gr-1 is
+
composed of a subunit from the Ly6 family and further classifies cells into M-MDSCs, which are CD11b +
+
Ly6G Ly6C , or PMN-MDSCs, which are CD11b Ly6G Ly6C lo[31,32] . Other markers suggested for more
+
hi
-
effective identification of murine MDSCs include CD84, CD244, fatty acid transporter protein 2 (FATP2)
+
-
lo/-
+
and CD36 [31,32] . On the other hand, human MDSCs are characterized by CD11b CD14 CD15 HLA-DR for
-
+
M-MDSCs and CD11b CD14 CD15 HLA-DR for PMN-MDSCs [31,32] . The low expression of HLA-DR
+
-
distinguishes M-MDSCs from monocytes [31,32] . CD33 can be used instead of CD11b, as it is expressed in high