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Page 10 of 17 Balakrishnan et al. J Cancer Metastasis Treat 2022;8:27 https://dx.doi.org/10.20517/2394-4722.2022.33

subtype promotes tumor development. TAMs had an M1-like phenotype and function at baseline in a
spontaneous mouse model of gastrointestinal stromal tumor (GIST) as well as in freshly obtained human
GISTs; however, treatment with imatinib, a KIT oncoprotein inhibitor, caused TAMs to become M2-like in
[93]
both mice and humans . In patients receiving platinum-based chemotherapy, the relevance of TAM
polarization is obvious. Chemoresistance is linked to increased levels of PGE2 (prostaglandin E2) and IL-6,
two inflammatory mediators mediated by COX. These inflammatory mediators induce monocyte
differentiation to the tumor-promoting M2 phenotype. Increased levels of activated STAT3 and lower levels
of activated STAT1 and STAT6, respectively, were associated with tumor-produced IL-6 and PGE2. In
breast and lung cancer xenograft models, myeloid bone marrow-derived cells (BMDCs), particularly
macrophages, rapidly accumulated in tumors after local irradiation with 21 Gy. SDF-1α/CXCL12, a
chemokine that supports the retention of BMDCs in the tissue, was found to be higher in the tumor two
days after local irradiation. Radiation combined with an inhibitor of the stromal cell-derived factor
1α (SDF-1α) receptor (AMD3100) significantly slowed tumor regrowth. These findings show that increased
SDF-1α expression by macrophages promotes tumor recurrence after radiation .
[94]
Role of myeloid cells in therapeutic response to immunotherapy
Most cancer cells have a large number of genetic and epigenetic alterations, which offer a large number of
TAAs that the host immune system can recognize, necessitating tumors to evolve particular immune
resistance mechanisms. Immunological-inhibitory pathways known as immune checkpoints, which
ordinarily control immune tolerance and minimize collateral tissue damage, are an essential immune
resistance mechanism. The immune-checkpoint receptor cytotoxic T lymphocyte-associated antigen 4
(CTLA-4), which reduces the amplitude of T cell activation, is particularly significant. Antibody inhibition
of CTLA-4 induced antitumor immunity in cancer mice models has been well studied. Melanoma activity
was proven in clinical investigations utilizing antagonistic CTLA-4 antibodies. In two randomized Phase III
trials, this treatment improved survival despite a high rate of immune-related harm. Anti-CTLA4
medication was the first to show a survival benefit in advanced melanoma patients . T cell effector
[95]
capabilities are limited within tissues by another immune-checkpoint receptor known as programmed
death 1 (PD-1). Tumor cells suppress antitumor immune responses in the TME by upregulating PD-1
ligands. Blocking the PD-1 pathway, according to early-stage clinical trials, causes long-term tumor
regression in a variety of tumor types. The expression of PD-1 ligands by tumor cells may correlate with
[95]
therapeutic response to PD-1 blocking .

In tumor immunotherapy, the current goal is to predict responders and evaluate the potential cause of
immunotherapy resistance in non-responders. The circulating and tumor resident myeloid cell population
may be used as a predictive biomarker for anti-CTLA-4 and anti-PD-1 therapy as myeloid cells are the
primary determinants of T cell response in antitumor immunity . Many studies have analyzed the impact
[96]
of tumor-infiltrating myeloid cells on cancer patient prognosis and the mechanisms of negative and positive
antitumor immune response modulation. Although the majority of the findings come from murine
malignancies, clinical evidence is beginning to emerge that links the presence of myeloid cells in TME to the
[96]
effectiveness of approved immune checkpoint therapies .
Among all myeloid cells, MDSCs have been shown to play a substantial role in determining the efficacy of
[97]
immunotherapy in human cancers . MDSCs play an important part in the formation of powerful
immunosuppression on both systemic and tumor levels, and some research has begun to shed light on their
[96]
potential as biomarkers of immune checkpoint inhibitor (ICI) response . Besides MDSCs, studies have
also shown roles for monocytes, tumor-derived neutrophils, or immature myeloid cells as predictors for
[97]
response to ICIs .