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Page 4 of 17 Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90

expressing CAFs is more prevalent in close proximity to PDAC cells whereas CAFs further away from
the tumor cells have increased expression of fibroblast activating protein (FAP). The two populations of
fibroblasts are mutually exclusive. FAP-positive CAFs secrete increased levels of cytokines [interleukin (IL)-1,
IL-6, IL-8, IL-10] and growth factors such as VEGF, insulin-like-growth factor (IGF1), PDGF, connective
tissue growth factor (CTGF) and FGF which stimulate angiogenesis, proliferation and metastasis [19,29] .
The PSCs also promote immunosuppression by recruiting myeloid-derived suppressor cells (MDSCs)
through the signal transducer and activator of transcription 3 (STAT3) pathway [30,31] . The MDSCs express
programmed death-ligand 1 (PD-L1) and the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptors
resulting in T cell tolerance. MDSCs also promote the development of regulatory T cells (Treg) through
the CD40 engagement in presence of inteleukin-10 (IL-10) and TGFβ. Besides immune regulation, MDSCs
also favor tumor progression via a non-immune mechanism by promoting tumor angiogenesis, cancer cell
[32]
stemness, aggressiveness, and invasiveness .
The complex interactions among the components of the PDAC TME make the tumor highly inductive to
angiogenesis, metastasis and treatment resistance.

THE CHALLENGING IMMUNE ENVIRONMENT IN PDAC
Immunogenicity is related to the degree of epitope structural difference between the tumor and normal
cells. Neoantigens, peptides generated from non-silent coding mutations in the cancer cell genome, are
[33]
highly immunogenic . Studies have shown that tumor mutation load is proportional to neoantigen
burden, which positively correlates with response to immunotherapy [34,35] . However, PDAC is characterized
by low tumor mutational burden (TMB) ranging from 10-60 encoded neoantigens in contrast to 100-1500
[36]
mutations per megabase expressed by other solid tumors that respond to immunotherapy . The limited
expression of neoantigens by PDAC leads to poor immune surveillance.

Additionally, the TME of PDAC is known to be immunosuppressive with reduced cytotoxic T cells (CD8+)
[37]
and T helper cells (CD4+) with increased Tregs, tumor-associated macrophages (TAMs), and MDSCs .
The location of T cells in PDAC also has important implications in resistance mechanisms. For example,
CD3+ T cells, which are either CD4+ or CD8+ T cells, have been identified more commonly at the invasive
front of PDAC with fewer cells detected in the center thereby excluded by malignant cells. Moreover, the
tumor infiltrating CD3+ T cells also cluster next to nests of malignant cells but are unable to interact with
[38]
tumor cells since they are trapped within the stromal tissue . Therefore, the overall regulatory immune
population of cells with exclusion of cytotoxic T cells along with the physical barrier created by a dense
stromal environment creates a non-immunogenic tumor that is often resistant to immune recognition and
killing. Nevertheless, the impact of T-cell infiltration on prognosis has shown inconsistent results with
some studies showing improved OS with increased intratumoral CD3+ T-cells, whereas other studies have
not shown an association between T-cell density and patient survival [38,39] .

The combination of an immunosuppressive environment and low TMB makes PDAC an “immune desert”
that is resistant to immunotherapies. However, it also suggests a potential treatment strategy by overcoming
low immunogenicity.

Immune check point inhibitors
The immune recruitment and response from T cells (CD4+ and CD8+) via antigen recognition in the
presence of malignant cells are controlled by inhibitory and stimulatory signals called immune checkpoints.
By expressing inhibitory ligands, tumor cells can evade immune surveillance [40,41] . The first immune
checkpoints discovered were CTLA4 and its ligands B7-1 and B7-2, and programmed cell death receptor 1
(PD1) and its ligands PD-L1 and PD-L2 [42,43] . Although immune checkpoint inhibitors (ICIs) such as
ipilimumab (CTLA4 inhibitor), pembrolizumab (PD1 inhibitor) and durvalumab (PD-L1 inhibitors) have