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Balakrishnan et al. J Cancer Metastasis Treat 2022;8:27 https://dx.doi.org/10.20517/2394-4722.2022.33 Page 11 of 17

Ipilimumab is a fully human IgG1 antibody targeted against CTLA-4 and has shown clinical efficacy in
metastatic melanoma in phase III clinical trials. The mechanism of action of ipilimumab is believed to be
linked to the enhancement of T cell-mediated killing of tumor cells. The exact mechanism by which anti-
CTLA-4 antibodies promote this immune-mediated tumor-killing is still not completely understood. Some
studies indicate induction of tumor-specific CD8+ T cells, while others have speculated that the effect might
be conveyed through the inhibition of regulatory T cells. In addition, treatment with ipilimumab has been
reported to reduce the frequency of MDSCs [98,99] . The long-term monitoring of Tregs, MDSCs, and tumor
antigen responses at three, six, and nine months following treatment with ipilimumab resulted in several
important findings. First, the significant increase in Treg (CD4+CD25hi+Foxp3+ and
CD4+CD25hi+CD39+) at six weeks reversed at three months. Second, CD4+CD25hiCD39+ Treg and HLA-
DR+lowCD14+ MDSCs may be baseline markers of immunotherapeutic benefit and warrant further study.
Finally, antigen-specific T cell immunity against shared TAAs (gp-100, MART-1, and NY-ESO-1) was
[100]
boosted with CTLA4 blockade . In another study focused on analyzing alterations in the myeloid cell
compartment and possible correlations of clinical outcomes with ICIs on MDSCs, it was reported that
[76]
MDSC frequency correlated with the outcome of anti-CTLA-4 treatment as indicated in Figure 3
although anti-CTLA-4 treatment is supposed to have a direct inhibitory role on T-effector cells and
T-regulatory cells, monocytes and MDSCs also express low levels of CTLA-4 and may be amenable to
CTLA-4 blockade. Anti-CTLA-4 treatment may have both T cell-specific and MDSC-specific roles; the
balance of inhibition of both T cell-specific and MDSC-specific pathways may be responsible for
determining the therapeutic response to CTLA-4 blockade.

In patients with Metastatic Urothelial Carcinoma (mUC), ICI treatment correlated with distinct changes in
PD1 and PDL1 expression by specific peripheral immune cell subsets such as cytotoxic T lymphocytes
(CTLs) and MDSCs. Higher PD1 expression by CTL following ICI therapy correlated with a higher
objective response rate. Further studies are required to validate immune biomarker expression in mUC and
explore its utility in guiding therapeutic decision-making and clinical trial eligibility/stratification .
[101]
Elevated PDL-1 expression has also been reported in tumor extracellular vesicles (TEVs) and correlates with
disease pathology in many human cancers. TEVs have also been shown to overexpress IL-3 Ra receptor.
Blockade of IL-3 R alpha signaling has been shown to enhance antitumor immune response by interfering
[99]
with epigenetic modifications that alter the transport of PDL-1 expression in TEVs .

CONCLUSION
The TME comprises diverse myeloid cells, particularly TAMs, TANs, DCs, and MDSCs, which contribute
to tumor progression, enhanced angiogenesis, metastasis, and immunotherapy resistance. Substantial
evidence indicates that tumor elimination may require multiple targets for achieving a satisfactory
therapeutic response. Myeloid cells have all the critical attributes of playing a regulatory role in tumor
biology. Therefore, deciphering the role of the individual myeloid cell population in TME is essential for
developing combinatorial therapeutic strategies in cancer. Immune cell-based therapies are gaining
substantial success, making them innovative approaches to cancer treatment. Understanding the crosstalks
that occur among the tumor-infiltrating myeloid cells and immune cells may be the first step in the
development of therapeutic strategies. Clinical trials of various immunotherapies, alone or in combination,
to enhance TME cells to repolarize their function to support cancer prevention are underway, but much
more research is required for optimum and successful implementation of myeloid cell-specific therapies.
Despite the advances in cancer treatment over the last few decades, resistance to traditional
chemotherapeutic agents and/or revolutionary targeted medications remains a major issue in cancer
therapy, accounting for the majority of relapses and one of the leading causes of cancer death. The
promising results of clinical trials combining ICIs with myeloid-targeting therapies reinforce the notion that