Page 309 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 23 Dendritic Cell Biology 257

+
release. cDCs can mediate transinfection of CD4 T cells through suggesting that inhibition of its activity may be a promising route
the formation of an infectious synapse, carrying the virus with or to restoring DC function in cancer. The tumor microenvironment
without infection of the DCs themselves. DCs express the coreceptors (TME) thus profoundly affects the function of infiltrating DCs and
CD4, CCR5, CXCR4, and the C-type lectin DC-SIGN necessary T cells, and it has recently been shown that overexpression of matrix
for binding or entry of HIV. HIV can infect DCs, but its replication metalloproteinase-2 (MMP-2) conditions DCs to produce low levels
+
+
is not as efficient as in CD4 T cells because of expression of the of IL-12 and to express OX40L, which biases antitumor CD4 T cells
203
viral restriction factor SAMHD1, a deoxynucleoside triphosphate toward suboptimal Th2 differentiation. This pathway has been
204
triphosphohydrolase. SAMHD1 functions to reduce cellular dNTP shown to involve the interaction of MMP-2 and TLR2 on DCs.
pools, thus reducing reverse transcription, although its restriction There can also be a failure of recruitment of DCs into the TME. For
195
activity may be separate from its trihydrolase activity. Under example, upregulation of a tumor-intrinsic WNT/β-catenin signaling
permissive conditions, however, HIV can induce the production of pathway is associated with poor T-cell infiltration into the TME of
205
the cyclic dinucleotide cyclic guanosine monophosphate-adenosine melanoma tumors. These tumors are defective in CCL4 produc-
monophosphate (cGAMP) via the cytosolic sensor cGAMP synthase tion, leading to a failure to locally recruit CD103/CD8α-lineage
+
+
(cGAS), suggesting that cGAMP can bypass the block of innate DCs, the murine equivalent of human CD141 DCs. CD103
196
immune responses against HIV. Under these conditions, HIV DCs are critical for the induction of T-cell immunity, and increased
induces type I IFN production in monocyte-derived DCs that is frequencies of these cells are correlated with improved clinical
dependent upon activation of the STING pathway. Recent studies outcomes. 206
have shown that polyglutamine binding protein 1 (PQBP1) directly
binds to reverse-transcribed HIV-1 DNA and interacts with cGAS
to generate cGAMP, which in turn primes an IRF3-dependent Immunotherapeutic Strategies and Clinical Trials
197
innate response. Virions formed in cGAMP-expressing cells have
the capacity to trigger a STING-dependent antiviral program in The past decade has seen increasing interest in clinical applications
newly infected cells. Indeed, cGAMP-loaded lentiviruses are able of DCs by harnessing the growing knowledge about DC biology.
to activate DCs, revealing a new way by which innate immunity It is becoming apparent that any effective vaccine must activate
198
can be transferred between cells. The cGAS pathway is the only and induce antigen presentation by DCs, the most potent cells at
signaling pathway triggered by HIV in monocyte-derived DCs stimulating T-cell immunity. A number of clinical trials (mostly
thus far. TLR7 and TLR8 do not appear to play a role in this phases I and II) have been completed describing the use of DCs in
respect. 199 cancer immunotherapy (e.g., non-Hodgkin lymphoma, malignant
The viral envelope protein gp120 can bind to CD4 and C-type melanoma, multiple myeloma, prostate cancer, renal cell carcinoma,
lectins such as DC-SIGN and mannose receptor, but the contribution breast cancer) and in the immunotherapy of human pathogens such
of each receptor to binding and internalization may vary, depending as HIV. Most of these studies have relied on monocyte-derived DCs,
+
on the particular type of DC encountered by HIV. Thus, although but a few have used DCs prepared from CD34 HPCs. A critical
DCs are not the main reservoir of HIV, the virus can “highjack” issue is antigen delivery to the DCs and the type of DC, with the
+
DCs to mediate its spread to CD4 T cells from mucosal tissues to nature of the antigen and the vehicle for delivery probably being
lymphoid organs. Nevertheless, although cDCs are only minimally decisive. DCs can be pulsed with defined antigens in the form of
activated by HIV, pDCs can become infected and strongly activated human leukocyte antigen–binding antigenic peptides or whole pro-
by HIV, causing them to secrete high amounts of IFN-α and other teins or the whole assortment of tumor antigens upon phagocytosis
+
antiviral molecules. This can inhibit the replication of HIV in CD4 of dying or opsonized autologous tumor cells. Artificial fusion of
T cells, suggesting that the two subsets play different and opposing DCs with tumor cells allows the generation of hybrid cells with
roles during HIV infection. However, pDCs may also function to characteristics of DCs but expressing the whole set of tumor antigens
downregulate the response by secreting TRAIL. 200,201 Furthermore, as well. Because autologous tumor cells are not always available from
the continuous secretion of IFN-α by pDCs stimulated by HIV patients with advanced disease, allogeneic tumor cells of the same
may be detrimental to the host by participating to chronic immune histologic origin expressing shared tumor antigens are also used for
+
activation and CD4 T-cell depletion. loading DCs.
Tumors also evolve mechanisms to negate the functionality of DCs themselves can also be genetically modified through
DCs. For example, the number of cDCs (but not pDCs) is reduced transfection. However, DCs are terminally differentiated nondivid-
in the blood of patients with cancer, and these numbers of DCs are ing cells and often challenging to transfect. Methods using RNA
restored upon surgical removal of the tumor, indicating a systemic electroporation and infection by recombinant viruses (lentivirus,
defect orchestrated by the tumor cells. Moreover, increased numbers poxvirus, herpes virus, and adeno-associated virus) lead to foreign
of imDCs are found in blood and tumor tissue, also displaying transgene expression in DC. Another strategy is to target DCs in
an impaired response to activation stimuli. A subset of immature situ using antibodies recognizing DC-specific molecules, such as
207
myeloid cells, composed of immature macrophages, DCs, granulo- DEC-205, as demonstrated in mouse models and more recently
208
cytes, and myeloid cells at early stages of differentiation, accumulate in patients with cancer. A phase II trial that involved priming by a
in the secondary lymphoid organs and tumors of tumor-bearing recombinant vaccinia virus encoding prostate-specific antigen and the
mice and presumably humans. These myeloid suppressor cells are “tricom” CD80, intercellular adhesion molecule-1), and lymphocyte
endowed with suppressive activity toward antitumor T cells through function–associated antigen 3 and boosting by a fowlpox virus gave
various mechanisms, such as regulation of arginine metabolism and promising clinical results in patients with prostate cancer. GM-CSF
release of ROS. In some tumors, IDO-expressing pDCs are found in was injected at the same time to further amplify immune stimulation.
significant numbers, thereby decreasing availability of tryptophan and This vaccine was designed to mimic antigen presentation by DCs,
generating tryptophan catabolites. IDO-expressing pDCs can activate even in an incomplete way, and induce significant overall survival
209
intratumoral (IT) Tregs. It seems that tumors impair early myeloid, benefit. A phase III study using this approach is currently underway.
and in particular DC, differentiation at a systemic level by secreting Because the activation state of antigen-presenting DCs is a
soluble factors such as VEGF, macrophage colony-stimulating factor, determining factor in shaping the ensuing immune response, genetic
IL-6, and IL-10. Macrophage-derived IL-10, for example, blocks engineering of DCs or triggering activating receptors also allows
IL-12 production by DCs and prevents the induction of tumor- enhancing their secretion, migration, and antigen presentation capac-
+
202
specific CD8 T cells. Many tumors constitutively express activated ity. Thus DCs can be activated by artificial TLR ligands (e.g., R848,
STAT3, a transcription factor partially implicated in the production which is a ligand for TLR7; unmethylated CpG oligonucleotides,
of these cytokines, the constitutive activation of which also impairs which are ligands for TLR9; or inflammatory cytokines, such as type
the secretion of proinflammatory cytokines. STAT3 is also respon- I IFNs, IL-1β, IL-6, or TNF-α) that can be used in a clinical setting
210
sible for abnormal differentiation of hematopoietic precursor cells, to activate DCs before injection or even in vivo. DCs can also be