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Current Clinical Landscape of Immunotherapeutic Approaches in... 349
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Fig. 4 CTLA-4 and PD-1 functions as two well-known inhibitory immune checkpoints. During
priming phase of T-cell activation occurring in lymph nodes, MHC/TCR (signal 1) and B7/CD28
(signal 2) interactions lead to transduce stimulatory signals to the T cell. In contrast, B7/CTLA-4
interaction induces an inhibitory signal in T cells. Monoclonal antibodies directed against CTLA-4
can reinvigorate T cells via disruption of CTLA-4/B7 connection. During effector phase occurring
in peripheral tissues, pancreatic cancer cells upregulate PD-L1 expression. PD-1/PD-L1 interaction
suppresses tumor-specific T cells, inducing an exhaustion phenotype in these cells. Monoclonal
antibodies directed against PD-1 and PD-L1 can revive T cells. TCR T-cell receptor, PD-1
Programmed cell death protein 1, PD-L1 Programmed death-ligand 1, CTLA-4 Cytotoxic
T lymphocyte antigen-4, MHC Major histocompatibility complex, DC: Dendritic cell. (This figure
was created by Biorender.com)
PD-1/PD-L1 Axis The PD-1/PD-L1 axis was studied in PC with other immune
checkpoint molecules after the successful clinical deployment of anti-PD-1/PD-L1
treatment in melanoma. The PD-1 molecule is a member of the B7-CD28 protein
family (Greenwald et al. 2005; Li et al. 2022). The exhaustion of T cells is linked to
the expression of PD-1, which is mostly found on effector CD4
(Keir et al. 2008; Ahmadzadeh et al. 2009; Sfanos et al. 2009). Tumor cells, MDSCs,
TAMs, and tumor-infiltrating DCs express the PD-1 ligands PD-L1 and PD-L2. In
addition to T cells and APCs, B and neoplastic cells express PD-1. Despite the low
level of PD-1 expression in naive T cells, prolonged antigen exposure activates the
PD-1/PD-L1 signaling pathway, ultimately leading to T-cell exhaustion. Since
PD-L1 is overexpressed by tumor cells, an engagement between PD-1 and PD-L1
recruits the tyrosine phosphatase SHP2, which dephosphorylates CD28 and blocks
T-cell activation (Li et al. 2022). PDAC has been shown to benefit with combination
immunotherapy with antibodies against PD-L1 and CCL5 (Wang et al. 2020). By
decreasing T
reg
PDAC microenvironment, the combination of anti-tumor necrosis factor receptor
2 (TNFR2) and PD-L1 mAbs led to tumor regression, improved OS, and induced
strong anti-tumor memory cells (Zhang et al. 2022a).
+
and CD8+T cells
and TAM infiltration and inducing CD8+T-cell activation in the
350 P. Farhangnia et al.
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Number of
participants Phase NCT identifier
340 I, II NCT03193190
93 II NCT02243371
61 II NCT03190265
Table 3 Clinical trials of immune checkpoint inhibitors and immunomodulatory agents in pancreatic cancer
Nab-Paclitaxel+Gemcitabine+Oxaliplatin
+Leucovorin+Cobimetinib+Fluorouracil
+PEGPH20+BL-8040 (CXCR4 antagonist)
+RO6874281+AB928+LSTA1
PD-L1, CD40,
VEGF, TIGIT, IL-6
receptor
Atezolizumab+Selicrelumab (CD40
agonist)+Bevacizumab+Tiragolumab
+Tocilizumab
Pembrolizumab PD-1 Onivyde+BL-8040 80 II NCT02826486
Pembrolizumab PD-1 CXCR4 antagonist BL-8040 18 II NCT02907099
Pembrolizumab PD-1 Olaptesed pegol 20 I, II NCT03168139
Immune checkpoint inhibitor and
immunomodulator Molecular target Combination therapy
Pembrolizumab PD-1 Defactinib 59 I, II NCT02758587
PD-L1, CD40 Dual immune checkpoints blockade 140 I NCT02304393
CSF1R, PD-1 – 313 I NCT02526017
Pembrolizumab PD-1 Paricalcitol 24 II NCT03331562
Atezolizumab (MPDL3280A)
+Selicrelumab (RO7009789)
Cabiralizumab (FPA008)+Nivolumab
(BMS-936558)
AMG820+Pembrolizumab CSF1R, PD-1 – 117 I, II NCT02713529
Durvalumab (MEDI4736) PD-L1 Pexidartinib (PLX3397) 48 I NCT02777710
Pembrolizumab PD-1 Acalabrutinib (ACP-196) 77 II NCT02362048
Ipilimumab CTLA-4 Gemcitabine hydrochloride 21 I NCT01473940
Nivolumab PD-1 Nab-Paclitaxel+Gemcitabine+Carboplatin 114 I NCT02309177
Durvalumab+Tremelimumab PD-L1, CTLA-4 Radiotherapy 65 I, II NCT02311361
Nivolumab+ Ipilimumab PD-1, CTLA-4 Radiotherapy 80 II NCT03104439
Cyclophosphamide+GVAX cancer vaccine 76 II NCT02451982
PD-1, CD137
(4-1BB), IL-8
Anti-PD-1 antibody PD-1 Radiotherapy 21 II NCT03374293
Nivolumab+ Urelumab (BMS-663513)
+BMS-986253
Nivolumab PD-1 CRS-207 vaccine+GVAX
+Cyclophosphamide
+Cyclophosphamide
Nivolumab+ Ipilimumab PD-1, CTLA-4 CRS-207 vaccine+GVAX
Current Clinical Landscape of Immunotherapeutic Approaches in... 351
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9 I NCT02930902
129 I, II NCT03214250
+Paricalcitol
30 II NCT03161379
202 II NCT03336216
(CD40 agonistic monoclonal antibody)
+Gemcitabine+Oxaliplatin+Leucovorin
+Irinotecan hydrochloride
58 II NCT02648282
+Radiotherapy
40 II NCT03006302
+Radiotherapy
25 I, II NCT03296137
207+GVAX cancer vaccine
+Cylophosphamide
therapy
– 358 I, II NCT03744468
TIM-3, PD-1,
LAG-3
Durvalumab+Bevacizumab PD-L1+VEGF CV301 vaccine+Capecitabine 8 I, II NCT03376659
Pembrolizumab PD-1 Gemcitabine hydrochloride+Nab-paclitaxel
Pembrolizumab PD-1 Defactinib+Gemcitabine 43 I NCT02546531
Nivolumab PD-1 Nab-Paclitaxel+Gemcitabine+APX005M
Cabiralizumab+Nivolumab+ CSF1R+PD-1 Nab-paclitaxel+Onivyde+Fluorouracil
Nivolumab PD-1 Cyclophosphamide+ GVAX cancer vaccine
Pembrolizumab PD-1 Cyclophosphamide+ GVAX cancer vaccine
Pembrolizumab+ IMC-CS4 PD-1+CSF1R Cyclophosphamide+ GVAX cancer vaccine 12 I NCT03153410
Pembrolizumab PD-1 Epacadostat (INCB24360)+CRS-
Ipilimumab+Nivolumab CTLA-4, PD-1 Proleukin+Cyclophosphamide+Fludara+TIL
Sym023 TIM-3 – 24 I NCT03489343
BGB-A425+Tislelizumab (BGB-A317)
+LBL-007
LY3321367+LY3300054 TIM-3, PD-L1 – 275 I NCT03099109
BMS-986258+Nivolumab TIM-3, PD-1 Human hyaluronidase PH20 92 I, II NCT03446040
PD-1 Programmed cell death protein 1, PD-L1 Programmed death-ligand 1, LAG-3 Lymphocyte activation gene-3, TIM-3 T-cell immunoglobulin and mucin
domain-containing protein 3, TIGIT T-cell immunoreceptor with Ig and ITIM domains, CTLA-4 Cytotoxic T lymphocyte antigen-4, CSF1R Colony stimulating
factor 1 receptor, VEGF Vascular endothelial growth factor, TIL Tumor-infiltrating lymphocyte
352 P. Farhangnia et al.
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CTLA-4 (CD152 ) The expression of CTLA-4 is largely found in Treg cells, and a
rise in the expression of CTLA-4 is shown as a consequence of T-cell activation. The
CD25-expressing helper T cells were shown to express CTLA-4. CTLA-4 functions
in a way that is intrinsic to the cell by suppressing the co-stimulatory signal, which in
turn hinders T-cell activation. Extrinsically, CTLA-4 acts by eliminating CD80 and
CD86 from APCs, which in turn reduces the response of CD8
the infiltration of CD4
pancreatic cancer microenvironment is controlled by the CTLA-4/CD80 pathway.
+
CD4
T-cell infiltration into the PDAC microenvironment was induced by
+
T cells (Li et al. 2022 ). The infiltration of T cells into the
+
T cells and regulates
disrupting the interaction between CD80 and CTLA-4 (Bengsch et al. 2017). A
study demonstrated for the first time that IL-6 and CTLA-4 blockade regressed
pancreatic tumors in a T-cell and CXCR3-dependent manner (Ware et al. 2023).
Lymphocyte-Activation Gene 3 (LAG-3) The LAG-3 signaling pathway is used
by cancer cells as a means of evading immune monitoring. Galectin-3 can decrease
the function of activated T cell s by binding to LAG-3 on their surface. Concurrently,
LAG-3 reduces the activity of plasmacytoid DCs, which are cells that deliver antigen
and trigger the development of naive T cells. T-cell proliferation can be modulated
by LAG-3, which also reduces memory and effector T-cell responses and increases
immunosuppression through T
cell-mediated suppression (Li et al. 2022). TILs
reg
that express LAG-3 have been linked to decreas ed OS in patients with pancreatic
cancer (Seifert et al. 2021). Anti-tumor immunity and a long-lasting response are
achieved in pancreatic cancer by blocking the immune checkpoints on T cells,
including LAG-3 and CD137 (4-1BB), and myeloid cell CXCR1/CXCR2 (Gulhati
et al. 2023 ).
T-Cell Immunoglobulin and Mucin Domain 3 (TIM-3) TIM-3 is responsible for
inhibiting the T-cell response by interacting with TAAs such as CEACAM-1 and
galectin-9 (Anderson et al. 2016). The formation of heterodimers between
CEACAM-1 and TIM-3, which limits the T-cell response by reducing the IL-2
and TNF-α expression, is correlated with T-cell exhaustion (Huang et al. 2015;
Anderson et al. 2016). Blocking TIM-3 and CEACAM-1 with antibodies increased
+
CD8
T-cell infiltration and IFN-γ production, which in turn reduced the development of the tumor (Zhu et al. 2005). Galectin-9, which is produced by tumor cells,
binds to TIM-3, which then activates down stream signaling. This c auses Ca
in helper T cells, which ultimately results in the death of these cells. Additionally,
tumor-infiltrating DCs that expressed TIM-3 had an interaction with nuclear high
mobility group box 1 protein (HMGB1), which decreased the effectiveness of
chemotherapy by lowering the immunogenicit y of nucleic acids generated from
the tumor cells (Chiba et al. 2012; Li et al. 2022). TIM-3 is responsible for limiting
anti-tumor immunity by mediating T-cell trogocytosis. The tumor burden was
reduced and survival was increased in two mice models of melanoma by blocking
TIM-3 and PD-1 simultaneously, which disrupted the trogocytosis of CD8
(Pagliano et al. 2022). Additionally, Bat3, a protein that binds to TIM-3 regulates
tolerogenic dendritic cell activity in an endogenous manner (Tang et al. 2023).
+
2
influx
+
TILs
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A study confirmed that TIM-3 was upregulated in pancreatic cancer cells and tissues.
Also, elevated levels of TIM-3 expression in pancreatic cancer tissues may be linked
to tumor cell invasion, metastasis, and recurrence (Peng et al. 2017). Furthermore,
there was no correlation between the TIM-3/Galectin-9 and patients’ prognosis
(NAKAYAMA et al. 2022).
T-Cell Immunoglobulin and ITIM Domain (TIGIT) TIGIT is expressed on the
cell surface and inhibits T-cell stimulation by triggering the development of immunomodulatory dendritic cells (Yu et al. 2008). TIGIT binds to its ligands, CD155 and
CD112, to provide signals that suppress T-cell activation. TIGIT may also suppress
the active signal to T cells by binding competitively to CD266 or CD96 with CD155
and CD112 (Stanietsky et al. 2009; Dougall et al. 2017; Farhangnia et al. 2022).
TIGIT interaction with CD155 also causes CD155 phosphorylat ion and release of
IL-10, which suppresses T-cell activation (Farhangnia et al. 2022). In pancreatic
cancer, the CD155/TIGIT axis fosters and sustains immune evasion (Freed-Pastor
et al. 2021). The effectiveness of vaccinations in a pancreatic cancer model is
improved by combination of TIGIT and PD-1 blockade (Peng et al. 2022). The
combination of TIGIT/PD-1 co-blockade and CD40 agonism reinvigorated pancreatic tumor cells-specific T lymphocytes (Freed-Pastor et al. 2021).
The V-Domain Ig-Containing Suppressor of T-Cell Activation (VISTA) The
B7 family member VISTA is homologous with the PD-L1 protein (Wang et al. 2011;
Gao et al. 2017; Ni and Dong 2017). VISTA is expressed in T lymphocytes and
endothelial cells (Hou et al. 2021). Pancreatic cancer is characterized by an
upregulation of the immunological checkpoint VISTA. CD68
+
macrophages are
the primary cell type expressing VISTA. It has been demonstrated that VISTA
activation suppresses cytoki ne generation by T cells isolated from metastatic pancreatic cancers (Blando et al. 2019). In light of this, anti-VISTA mAbs may serve as
a useful immunotherapeutic approach for patients with pancreatic cancer (Blando
et al. 2019; Hou et al. 2021). Furthermore, in pancreatic cancer, a better prognosis is
linked to VISTA expression (Hou et al. 2021).
3.4 Cancer Vaccines
Therapeutic cancer vaccines cause tumor regression, eliminate any remaining malignancy, generate long-lasting anti-tumor memory, and prevent any undesirable,
non-specific effects (Fig. 5). Vaccines against cancer often entail the exogenous
delivery of tumor antigens together with adjuvants or even DCs themselves that
stimulate the immune system (Saxena et al. 2021). Table 4 presents the classification
of cancer vaccines in the context of pancreatic cancer studies. Furthermore, Table 5
provides clinical trials of cancer vaccines.
Whole Tumor Cell Vaccines The use of a complete tumor cell vaccination is a
straightforward and uncomplicated method of tumor immunotherapy. Both CD4
+
354 P. Farhangnia et al.
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Fig. 5 Principles and mechanisms of action of cancer vaccines. Following injection of tumor
antigens, these molecules are taken up and presented by APCs, particularly dendritic cells. As a
result, naïve or memory CD4
migrate to tumor microenvironment, where they recognize and eradicate antigen-expressing tumor
cells. TCR T-cell receptor, IL-2 Interleukin 2, TNF Tumor necrosis factor, IFNγ Interferon-gamma,
APC Antigen-presenting cell, IL-12 Interleukin-12, MHC Major histocompatibility complex. (This
figure was created by Biorender.com)
+
and CD8+T cells activated by APCs. These activated lymphocytes
helper T-cell and CTL epitopes are present in the tumor cell vaccination. One
of these vaccines is Algenpantucel-L (NLG0205). Allogeneic cancer cell lines
transduced with α-1,3-galactosyltransferase are used to produce the vaccine
Algenpantucel-L. α-1,3-galactosyltransferase synthesizes α-galactosylated epitopes
on cell surface proteins with potential anti-tumor activity (Bot et al. 2018; Tekkesin
and Tetik 2019). A phase II trial showed that when Algenpantucel-L was combined
with the adjuvants gemcitabine and 5-fluoruracil, 1-year survival rates of 86%,
2-year survival rates of 51%, and 3-year survival rates of 42% were achieved
(Hardacre et al. 2013). However, a study revealed that patients with locally advanced
or borderline resectable PDAC who received standard of care, neoadjuvant chemotherapy, and chemoradiation did not benefit from Algenpantucel-L immunotherapy
(Hewitt et al. 2022).
Dendritic Cell Vaccines TAAs or TAA-coding or tumor-derived mRNA were
loaded into DCs separated from the patient’s peripheral blood and then re-infused .
The modified DCs then move on to the lymph nodes, where they deliver antigens to
T lymphocyte s while simultaneously providing co-stimulatory signals (McCormick
et al. 2016). Autologous monocyte-derived DCs loaded with mRN A encoding for
CEA resulted in all patients in a trial of 3 patients with stages I/II pancreatic cancer
staying alive and disease-free more than 2.5 years after diagnosis (Morse et al. 2002).
Apheresis was used to collect DCs from 7 patients with stage III/IV pancreatic
cancer, and these DCs were then pulsed with MUC-1 peptide. In these patients,
Table 4 Classification of cancer vaccines in pancreatic cancer treatment
https://t.me/med1917
Type of
vaccine Mechanism Candidate vaccine Reference
Whole
tumor cell
vaccine
Peptide
vaccine
DC
vaccine
DNA
vaccine
mRNA
vaccine
Viral/
bacterial
vectorbased
vaccine
DC Dendritic cell, TSA Tumor-specific antigen, TAA Tumor-associated antigen, MSLN Mesothelin,
HSP Heat-shock protein, FAPα Fibroblast activation protein alpha, MUC-1 Mucin-1, ENO1
α-Enolase, VNTRn Variable number tandem repeat, LAK Lymphokine-activated killer, VEGFR
Vascular endothelial growth factor receptor, CEA Carcinoembryonic antigen
Irradiated tumor cells
expressing TAAs
Epitope, peptide, or
protein expressed by
pancreatic tumor cells
DCs are pulsed with TAAs
or TSAs.
Administration of
genetically engineered
DNA cells to produce an
antigen, resulting in a
protective immunological
response.
mRNA encoding TSAs
and TAAs
Immunogenic viral or
bacterial vectors
expressing TSAs and
TAAs
Algenpantucel-L
(NLG0205)
GVAX Lutz et al. 2011; Le et al.
RAS oncogenebased vaccine:
GI-4000
Gastrin-based
vaccine: G17DT
Telomerase-based
vaccine: GV1001
VEGFR-based
vaccine: VXM01
Survivin-based
vaccine:
AYACNTSTL
HSP-peptide
complex-based
vaccines:
HSPPC-96
MUC-1-pulsed DCs Rong et al. (2012)
DC vaccine plus
LAK cells
DCs loaded with
mRNA encoding
CEA
ENO1 DNA vaccine Cappello et al. (2013),
MUC-1-VNTRn Gong et al. (2017)
Chimeric DNA
encoding FAPα and
survivin
RO7198457 NCT04161755
Live-attenuated
Listeria
Monocytogenes
encoding MSLN:
CRS-207
Heat-killed whole
cell vaccine of
Mycobacterium
obuense: IMM101
Hardacre et al. (2013)
(2015)
Gjertsen et al. (1995, 2001),
Wedén et al. (2011), AbouAlfa et al. (2011), Cohn
et al. (2018), Muscarella
et al. (2021)
Brett et al. (2002), Gilliam
et al. (2012)
Bernhardt et al. (2006),
Middleton et al. (2014)
Miyazawa et al. (2010),
Niethammer et al. (2012),
Schmitz-Winnenthal et al.
(2015)
Kameshima et al. (2013)
Maki et al. (2007)
Kimura et al. (2012)
Morse et al. (2002)
Mandili et al. (2020)
Geng et al. (2022)
Le et al. (2015)
Dalgleish (2015), Dalgleish
et al. (2016)
356 P. Farhangnia et al.
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Pembrolizumab (anti-PD-1 mAb) 70 I NCT03948763
A tetravalent mRNA cancer
,
G12V
G12C
vaccine targeting mutations in the
KRAS gene
29 I NCT04161755
Atezolizumab (anti-PD-L1 mAb)
+FOLFIRINOX
vaccine, in which mRNA encoding
certain TAAs is taken up by APCs,
and prompts immunological
responses from both cytotoxic and
memory T cells.
– 18 I NCT04853017
A peptide-based cancer vaccine
G12R
containing amphiphile KRAS
peptides plus CpG adjuvant
– 25 I NCT05013216
eliciting immune response against
30 I NCT04117087
Nivolumab (anti-PD-1 mAb)
mutant KRAS
Inducing immune response against
,
G12V
+Ipilimumab (anti-CTLA-4
mutant KRAS and enhancing
,
G12A
G12R
mAb)
immune responses through ICB
– 12 I NCT03956056
T-cell immune responses
+
Stimulating tumor-specific CD4+and CD8
150 I NCT02600949
Imiquimod (TLR7 agonist)+
Pembrolizumab+ Sotigalimab
(APX005M; CD40 agonist
immune responses
antibody)
, KRAS
, KRAS
G12D
G13D
KRAS
KRAS
Vaccine Molecular target Mechanism Combination therapy Participants Phase NCT identifier
mRNA-5671/
Table 5 Active clinical trials of cancer vaccines in pancreatic cancer
V941
RO7198457 TAAs A personalized mRNA cancer
, KRAS
G12D
ELI-002 KRAS
KRAS A peptide-based cancer vaccine
KRAS peptide
G12C
vaccine+Poly-
ICLC adjuvant
, KRAS
, KRAS
G12D
KRAS
KRAS
, KRAS
G13D
Prioritized neo-antigens
KRAS
Neo-antigen
and personalized
mesothelin epitopes
peptide vaccine
+Poly-ICLC
adjuvant
TAAs Stimulating tumor-specific T-cell
Personalized
synthetic
peptide vaccine
ICB Immune checkpoint blockade, TAA Tumor-associated antigen, APC Antigen-presenting cell, TLR7 Toll-like receptor 7, mAb Monoclonal antibody, PD-1
Programmed cell death protein 1, PD-L1 Programmed death-ligand 1, CTLA-4 Cytotoxic T lymphocyte antigen-4
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injection of MUC-1-pulsed DCs was safe and effective at eliciting an immune
response to the MUC-1 (Rong et al. 2012).
Peptide Vaccines It has been revealed that the anti-cancer vaccine candidate
GV1001 (created from a peptide derived from a reverse-transcriptase portion of
telomerase, or hTERT), possesses surprising cell-penetrating peptide characteri stics
(Günes and Rudolph 2013; Mocellin et al. 2013; Kim et al. 2016). A significant
immune response was observed in 24 (63%) of 38 patients in a phase II study of
GV1001 for advanced pancreatic cancer; immune responders had a better median
survival (216 days) than non-responders did (88 days) (Bernhardt et al. 2006).
However, in a phase III clinical trial, no significant improvement in OS was observed
when chemotherapy was combined with the GV1001 vaccine (Middleton et al.
2014). Another peptide cancer vaccine was KIF20A-66. This peptide is an
HLA-A24 restricted epitope generated from KIF20A, a protein that is highly
transactivated in pancreatic cancer and is a member of the kinesin superfamily,
protein 20A. The results of a phase I/II trial showed that the immunization with the
KIF20A-66 peptide was well-tolerated. mOS was 142 days, while the median PFS
was 56 days (Asahara et al. 2013).
DNA Vaccines DNA vaccination targeting α-Enolase (ENO1), a TAA that is
overexpressed in PDAC, effectively prolongs survival in mice that spontaneously
develop PDAC (Cappello et al. 2013). Additionally, chemotherapy with gemcitabine
for pancreatic cancer improves the efficacy of ENO1 DNA vaccine against TAAs,
including ENO1, glyceraldheyde-3-phosphate dehydrogenase (G3P), keratin, type II
cytoskeletal 8 (K2C8), and far upstream binding protein 1 (FUBP1) (Mandili et al.
2020). Another DNA vaccine named mucin 1-variable number tandem repeat
(MUC1-VNTRn) showed robust cytotoxic effects in both in vivo and in vitr o
investigations (Gong et al. 2017). A chimeric DNA vaccine against human fibroblast
activation protein alpha (FAPα) and survivin was developed by Geng and
colleagues. DNA vaccination in mice with pancreatic tumors not only decreased
the number of immunosuppressive cells, but also increased the number of TILs,
reshaping the TME to better accommodate anti-tumor immune responses (Geng
et al. 2022 ).
mRNA Vaccines Personalized mRNA cancer vaccines contain mRNA encoding
certain TAAs. Afterwards, the mRNA is internalized and the corresponding peptide
antigens are displayed by APCs, leading to the triggering of immune responses from
both cytotoxic and memory T cells (Fig. 6). RO7198457 (BNT122) is an mRNA
cancer vaccine designed to stimulate T-cell-mediated immune responses against
neo-antigens. Several clinical trials are planned in patients with different cancers,
including pancreatic cancer (NCT04161755), solid tumors (NCT03289962), melanoma (NCT03815058), and colon cancer (NCT04486378).
358 P. Farhangnia et al.
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Fig. 6 Principles and mechanism of action of mRNA cancer vaccines. Following injection of
mRNA cancer vaccine, mRNA encoding tumor-specific antigen (TSA) or tumor-associated antigen
(TAA) are taken up by dendritic cells (DCs) via endocytosis. Afterward, DCs translate mRNA to
tumoral proteins. Thereafter, naïve CD4
antigens-presenting DCs in a MHC-II and MHC-I-reliant manner, respectively. Thus, effector
T cells can affect tumor growth and induce apoptosis in cancerous cells. TNFα Tumor necrosis
factor alpha, IFNγ Interferon gamma, IL-2 Interleukin-2, MHC Major histocompatibility complex,
TCR T-cell receptor. (This figure was created by Biorender.com)
+
and CD8+T cells are primed and activated by tumor
3.5 Immunotherapeutic Strategies Based on Targeting Myeloid
Cells and CAFs
In this section, we strive to highlight the therapeutic aspects of targeting myeloid
cells in pancreatic cancer. Also, Table 6 provides clinical trials of immunotherapies
based on targeting myeloid cells and CAFs.
3.5.1 Targeting Macrophages
Macrophages are more prevalent in PDAC and play a role in tissue healing,
promoting the proliferation of epithelial cells and even promoting tumor development (Mitchem et al. 2013). However, macrophage depletion approaches in solid
tumors are ineffective because other myeloid cell populations tend to rise to compensate (Twyman-Saint Victor et al. 2015). A novel treatment paradigm might come
from therapies that retrain macrophages to engulf and destroy living tumor cells.
Antibodies that stimulate the phagocytic program in macrophages were initially
discovered in PDAC treated with agonistic anti-CD40 (Beatty et al. 2011; Hosein
et al. 2022). Original research suggested that anti-CD40 antibody only affected
macrophages, but further studies have revealed that it also stimulated DCs and
improved T-cell priming (Long et al. 2016; Byrne and Vonderheide 2016; Morrison
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