Page 71 - Read Online

Chi et al. J Cancer Metastasis Treat 2020;6:43 I http://dx.doi.org/10.20517/2394-4722.2020.90 Page 13 of 17

In summary, PDAC responds poorly to immune checkpoint blockade with both anti‐CTLA‐4 and anti‐
PD1/anti‐PD‐L1 immunotherapies. This could be due to the presence of dense desmoplasia and tumor
microenvironment made up of extracellular matrix proteins, fibroblasts, endothelial cells, and immune
cells. It has been clearly indicated by preclinical studies that the tumor microenvironment has abundant
immunosuppressive cell types and few effector T cells.

In addition, cancer associated fibroblasts (CAF) especially FAP positive CAF have been shown to be
important in mediating immunosuppression in the PDAC tumor microenvironment. Although treating
PDAC with immunotherapy alone has not been very successful, various combination strategies of
immunotherapies (including CAR-cells and immune check point inhibitors) with therapeutic vaccine and/
or radiation therapies to improve immunogenicity of PDAC are ongoing. The multipronged approach
to treating PDAC has led to various trials targeting tumor DNA repair (PARP inhibitors), and tumor
metabolism (mitochondrial inhibitor). Novel agents such as FAK inhibitors, CTGFs are also being studied
in early phase trials. The results of these studies are highly anticipated and some trials hold promise to
advance into later-phase clinical trials. It is hoped that the results from these studies will eventually improve
the outcome for pancreatic cancer patients.

TAKE HOME POINTS
Patients with pancreatic cancer show poor response to chemotherapies and ICI due to its unique
immunosuppressive tumor microenvironment with extensive desmoplasia.

The complex interactions among the components of PDAC TME (fibroblasts, endothelial cells, and
extracellular matrix proteins, tumor‐associated macrophages, MDSC, and Treg cells) lead to tumorignesis,
chemo-resistance, and immune suppression although some recent studies also show evidence of tumor-
restraining role of the desmoplasia.

PDAC is characterized by low TMB due to limited expression of neoantigens and leads to poor immune
surveillance and poor response to ICIs. However, a small subset (1%-3%) of PDAC patients with dMMR or
MSI-H tumors showed high response rate to single agent pembrolizumab.
(1) ChemoXRT may increase immunogenicity in PDAC, which can sensitize tumors to immunotherapy.
Multiple phase I/II trials with combination chemoXRT and immunotherapy are ongoing.
(2) GVAX, vaccine developed from PDAC tumor associated antigens, showed T-cell mediated antitumor
activity in preclinical and early phase clinical trials. It is now under investigation in combinations with
ICIs. There are various ongoing early phase trials using viral vector, peptide based vaccines, DNA based
vaccines, yeast-based vaccines and dendritic cell-based vaccines.
(3) Strategies with various targeted therapies are being explored in clinical trials targeting tumor DNA
repair (PARP inhibitors), and tumor metabolism (mitochondrial inhibitors).
(4) Novel agents such as FAK inhibitors and CTGF are also being studied in early phase trials.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Chi J, Patel R, Rehman H, Goyal S, Saif MW
Performed data acquisition, as well as provided administrative, technical, and material support: Chi J, Patel
R, Rehman H, Goyal S, Saif MW

Availability of data and materials
Not applicable.