Page 19 - TD-1-1

Tumor Discovery Monocytes from single-cell analysis

collected from baseline and after 12 weeks of anti-PD-1 melanoma patients. Patients with melanoma whose
therapy. After single-cell mass cytometry along with frequency is above the cutoff values of myeloid index
clustering analyses, researchers characterized superficial score (MIS) are stratified according to their prognosis. In
molecular markers and intrinsic gene expression between addition to having been confirmed in the validation set,
responders and non-responders, and ultimately found the MIS was negatively related to survival, independent
−
hi
+
that the level of CD14 CD16 HLA-DR monocytes was a of the type of therapy, and was not interfered with by the
strong predictor of progression-free survival in response clinical prognostic factors. MIS hazard ratio (HR) was
to anti-PD-1 immunotherapy. By analyzing 53 standard remarkably superior to that of lactate dehydrogenase,
clinical parameters and the levels of classical monocytes tumor burden, and neutrophil-to-lymphocyte ratio.
via Cox proportional-hazards model, they found that These results demonstrated that the levels of monocytes
immature granulocytes and classical monocytes are the are helpful for identifying advanced melanoma patients
only variables tightly associated with progression-free and making therapeutical choices [135] .
survival.
(B) Monocytes and its derived APCs are related to the efficacy of
FlowSOM can be used to identify CD14 (CD11b HLA- PD-1 checkpoint blockade
+
+
DR ) myeloid cells and CD14 (CD11b HLA-DR ) myeloid As a result of the expression of PD-1, the phagocytosis
lo
hi
+
−
cells. According to the comparison of cluster frequencies of tumor cells by TAM is inhibited, thereby increasing
in healthy donors, non-responders, and responders from tumor progression both in mouse tumor models and in
60 data sets, researchers observed a higher frequency of humans with cancer. Blockade of PD-1/PD-L1 in vivo
CD14 myeloid cells in responders than in non-responders. benefits macrophage phagocytosis, restricts tumor growth,
+
Besides, CD14 myeloid cells were abundant in cancer and prolongs survival in mouse cancer models through a
-
patients, but there was no significant difference between macrophage-dependent fashion [136] .
responders and non-responders. With the application of
the machine-learning algorithm CellCnn, they further Schetters et al. recently demonstrated that the moDCs in
detected the core signature of this subpopulation, that TME express abundant costimulatory molecules to interact
is, CD14 CD33 HLA-DR ICAM-1 CD64 CD141 with lymphocytes, which can only be found in responding
+
+
+
+
hi
+
CD86 CD11c CD38 PD-L1 CD11b monocytes, which mouse melanoma model after anti-PD-1 therapy. Besides,
+
+
+
+
+
showed a significant overlap with the CD14 CD16 HLA- they used scRNA-seq and other techniques to investigate
+
−
hi
DR cluster characterized by FlowSOM. More specifically, the two differentiation pathways of monocyte. moDC has
the level of classical monocyte >19.38% before the initiation been found to be significantly abundant in responding
of anti-PD-1 therapy indicates a better responsiveness to patients, while macrophage-prone monocytes infiltration
anti-PD-1 therapy and a longer survival for melanoma was found in the nonresponsive patients [130] . This indicates
patients . However, RNA sequencing showed no notable that macrophages may regulate other DCs or promote
[6]
+
difference in this monocyte cluster between the responders CD8 T cells through other pathways. In addition, another
and non-responders. This indicates that the responsiveness study revealed the suppressive role of monocytes in HCC.
might depend on the number of CD14 CD16 HLA-DR The objective response rate was relatively high (about 40 –
−
hi
+
monocytes. 50%) in patients with solid tumors such as melanoma and
lung cancer compared to merely 17% in those with HCC [137] .
Emerging data suggest that the expression of the The authors found that M-MDSCs facilitate tumor growth.
chemokine CXC motif ligand 9 (CXCL9) by TAMs regulates As for the intrinsic mechanism, human hepatic stellate
the recruitment and positioning of CXC motif chemokine cell (HSC) caused monocytes accumulation in the fibrotic
receptor 3 (CXCR3)-expressing stem-like CD8 T cells microenvironment through p38 MAPK signaling pathway.
(T stem and antitumor immunity). The CXCL9 expression Since the bromodomain and extraterminal domain
of TAM should be considered in the determination of the (BET) decreased the M-MDSC filtration and enhanced
efficacy of therapies that enhance anti-PD-L1 response the efficacy of ICB therapy, which also makes it rational
rates. In another word, enhancing the level and function to implement clinical trials of combination therapy of
of CXCL9-expressing TAMs can be synergistic with anti- BET bromodomain and PD-L1 co-blockade [138] . IFN gene
PD-(L)1 therapy to inhibit tumor growth. Except for T stem therapy led to single-cell transcriptional reprogramming
recruitment, the potential functions of these cells deserve of tumor-associated myeloid cells, and this counteracted
further exploration [134] .
the expansion of immunosuppressive myeloid cells
MDSC is thought to be the cornerstone of cancer- induced by leukemia, which were shown by bulk single-
related immunosuppression as it can influence the cell transcriptome analyses. Thus, it has been suggested
response to therapy and the disease outcomes in that IFN gene therapy probably can enhance the efficacy
Volume 1 Issue 1 (2022) 10 https://doi.org/10.36922/td.v1i1.4