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More: targeting TAM repolarization to the M1 in TAMS a cancer therapeutic targetout of China Shaping Polarization Of Tumor-Associated Macrophages In Cancer Immunotherapy
Different stimuli can polarize macrophages into two basic types, M1 and M2. Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are composed of heterogeneous subpopulations, which include the M1 anti-tumor and M2 pro-tumor phenotypes. TAMs predominantly play a M2-like tumor-promoting role in the TME and regulate various malignant effects, such as angiogenesis, immune suppression, and tumor metastasis; hence, TAMs have emerged as a hot topic of research in cancer therapy. This review focuses on three main aspects of TAMs. First, we summarize macrophage polarization along with the effects on the TME. Second, recent advances and challenges in cancer treatment and the role of M2-like TAMs in immune checkpoint blockade and CAR-T cell therapy are emphasized. Finally, factors, such as signaling pathways, associated with TAM polarization and potential strategies for targeting TAM repolarization to the M1 pro-inflammatory phenotype for cancer therapy are discussed.... TAMs are one of the most common immune cells that infiltrate the TME.
These cells originate from two main sources: bone marrow peripheral
monocytes and embryos that reside in different tissues, the latter
including Kupffer cells in the liver, alveolar macrophages in the lungs,
microglia in the brain, and osteoclasts in the bone (7).
Peripheral blood circulating monocytes, which are recruited into the
TME by circulating tumor-secreting factors and transform into
macrophages, are generally thought to be the main source of TAMs. In
contrast, a small number of macrophages are derived from early
tissue-resident macrophages originating in the yolk sac or fetal liver (8).
Broadly speaking, monocytes are attracted by cytokines, such as colony
stimulating factor (CSF)-1 and CCL-2, and subsequently polarize into
TAMs in the TME. These polarized TAMs usually express M2 macrophage
markers and cytokines, such as mannose receptors (CD206), scavenger
receptor (CD163), VEGF, and IL-10, and exhibit tumor-supporting effects,
and are hence called M2-like TAMs. Conversely, few TAMs in the TME
express CD86 and CD80 markers and are termed as M1-like TAMs, and
typically exhibit anti-tumor effects (9). 3 Cancer Immunotherapy and M2-Like TAMsGiven that traditional cancer treatment strategies, such as radiotherapy, chemotherapy, and surgical excision, are associated with challenges of resistance and recurrence, a variety of immune checkpoint and checkpoint blockade immunotherapy strategies have been proposed and are starting to shed light on the treatment of various cancer types. These immune checkpoint-associated therapies, also known as immune checkpoint blockade (ICB) or immune checkpoint inhibitors (ICIs), include targeting and antagonizing cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1), and its ligands (programmed death ligand 1 [PD-L1] and 2 [PD-L2]) (25). Moreover, chimeric antigen receptor (CAR)-T cell therapy is another immunotherapy strategy that has achieved tremendous breakthrough in recent years and is mainly applied in non-solid tumors, such as leukemia and lymphoma (26). TAMs are essential components of the TME and play a prominent role in these therapeutic processes and pave the way for the creation of new therapeutic approaches. In this section, recent advances and challenges in cancer treatment as well as the role of M2-like TAMs in ICB and CAR-T cell therapy are discussed. 3.1 Recent Advances and Challenges in Cancer TreatmentCTLA-4 is a receptor located on the surface of T cells that dampens T cell activity and promotes tumor proliferation. Mechanistically, CTLA-4 prevents uncontrolled expansion of activated T cells by competitively binding to CD80/CD86 receptors on CD28-expressing dendritic cells. Similarly, PD-1 is another immune checkpoint receptor that is often expressed on the surface of tumor-infiltrating lymphocytes, while its ligands PD-L1 and PD-L2 are highly expressed on tumors; the interaction of PD-1 with PD-L1/PD-L2 can lead to a diminished immune response (25). Hence, blocking immune checkpoints, such as CTLA-4, PD-1, and PD-L1/PD-L2, using ICB drugs has become a widely investigated strategy for cancer treatment. The CTLA-4 antibody ipilimumab and anti-PD-1 antibodies, pembrolizumab and nivolumab, have been approved by the United States Food and Drug Administration as therapeutic agents for patients with melanoma (27). PD-L1 antibodies durvalumab and avelumab have also been approved for use in different cancers. However, despite the unprecedented success of ICB, its efficacy against “cold” tumors, such as glioblastoma (GBM), remains elusive, in part due to TIM-3 upregulation and the blocking effect of the blood–brain barrier (28). In addition, due to a multitude of host endogenous or exogenous factors, the therapeutic response to ICB in cancer is often restricted, either effective only in specific tumor types or in selected patients. Furthermore, the prevalence of immune-related adverse events associated with ICB therapy remains high and the underlying mechanisms remain unclear and require further study. 3.2 Role of M2-Like TAMs in ICB and CAR-T Cell TherapyThe application of ICB drugs and the novel concept of harnessing the “CAR” devices to active and direct T cells has brought a considerable breakthrough in the field of oncology. Given that the limitations of these two therapeutic approaches exist primarily in solid tumors rather than in hematologic tumors, a better understanding of the mechanisms underlying resistance in solid tumors may help improve the modalities and efficacy of immunotherapy. With this regard, the activity of M2-like TAMs in the TME is highly correlated with immune downregulation and resistance to these treatments, which needs to be urgently addressed. 5 ConclusionTAMs located in the TME have the following characteristics: 1) TAMs have an M2-like macrophage phenotype and can exert anti-inflammatory and pro-tumor effects; 2) studies have shown that TAMs decrease the efficacy of ICB and CAR-T cell therapy; 3) TAM polarization is regulated by the various signaling pathways and regulating these pathways can effectively alter TAM phenotype; and 4) strategies targeting TAM repolarization, such as exosomes, bacterial therapy, NPs, and CAR-M therapy, show potential in the treatment of solid tumors. Paradigm-shifting discoveries of targeted TAM polarization in tumor immunotherapy and their remarkable effect on some tumors have made it a hot research topic. Nevertheless, almost all studies have been conducted at the preclinical stage. It is important to acknowledge that most drugs targeting TAMs still face difficulties, such as transport barriers, complex preparation methods, and unstable drug forms. In conclusion, research on TAM repolarization is still in the preliminary stages and several different targeting approaches are under investigation. The efficacy of these approaches in combination with other anti-tumor strategies in different tumors warrants further investigation. |
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