Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

Hino, Christopher; Pham, Bryan; Park, Daniel; Yang, Chieh; Nguyen, Michael H K; Kaur, Simmer; Reeves, Mark E.; Xu, Yi; Nishino, Kevin; Pu, Lu; Kwon, Sue Min; Zhong, Jiang; Zhang, Ke K.; Xie, Linglin; Chong, Esther G; Chen, Chien-Shing; Nguyen, Vinh; Castillo, Dan Ran; Cao, Huynh

doi:10.3390/biomedicines10061410

Cited by 12 publications

(9 citation statements)

References 151 publications

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“…With the development of oncology, immunology, cell biology, molecular biology, and other related disciplines in recent years [52], tumor immunotherapy has received increasing attention [53]. However, due to the complex process of tumor immunity, the combined effect of multiple mechanisms affects the e cacy of immune checkpoint inhibitors (ICIs) [54].…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis reveals potential for synergy between SERPINA1 molecular targeting and macrophage-related immunotherapy

Fu¹,

Miao²,

Xue³

et al. 2022

Preprint

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Background The immune response can be modulated by autophagy to alter tumor growth. SERPINA1 is not only an autophagy-related protein but also a serine protease inhibitor with the potential for immunotherapy and targeted drug therapy. Methods Based on the latest multi-omic databases, we evaluated SERPINA1 mRNA and protein expression levels, prognostic value, methylation and mutation, signaling pathway, and gene ontology analysis and explored their relevance. The relationship between SERPINA1 expression and immune and drug sensitivity was also analyzed. Single-cell sequencing was used to validate the function and immunity in different cancers. Results Many tumors are associated with abnormal SERPINA1 expression and a poor prognosis. According to our study, DNA methylation, gene mutations, and post-translational modifications of SERPINA1 were significantly and positively correlated with its expression levels in breast cancer as a diagnostic marker. In addition, we observed that SERPINA1 positively correlates with macrophages and was able to stimulate M2 macrophage polarization, It was found that SERPINA1 was associated with macrophages in glioma immune microenvironments. Conclusions Considering that SERPINA1 plays a role in cancer progression, SERPINA1 may be a new promising target for immunotherapy and drug target therapy.

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Section: Discussionmentioning

confidence: 99%

Pan-cancer analysis reveals potential for synergy between SERPINA1 molecular targeting and macrophage-related immunotherapy

Fu¹,

Miao²,

Xue³

et al. 2022

Preprint

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“…Despite the lack of a consensus, in patients who are not considered candidates for intensive therapy, following regimens are often used in the context of clinical trials: Azacitidine or decitabine + venetoclax combination, low dose cytarabine + venetoclax combination, azacitidine + ivosidenib combination (AML with IDH1 mutation), ivosidenib monotherapy for very frail patients (AML with IDH1 mutation) or best supportive care including hydroxyurea for patients who cannot tolerate or refuse any anti-leukemic therapy (20). To be considered in remission, bone marrow biopsy should show normocellular bone marrow while blasts should not exceed 5%; yet many patients develop relapsed and refractory diseases despite therapeutic options (22). Stem cell transplantations are reported to decrease the risk of leukemia relapse more than the standard chemotherapeutic approaches, yet they are also likely to lead to severe complications (23).…”

Section: Current Treatment Strategies In Acute Myeloid Leukemiamentioning

confidence: 99%

“…Besides the abovementioned therapeutic interventions, other immunotherapeutic strategies in AML include immune checkpoint blockade, bispecific T cell engagers (BiTE), chimeric antigen receptor T cells (CAR-T) and tissue infiltrating lymphocytes (TIL) are under investigation (19,22). As extensively described in the literature, the expression of inhibitory checkpoint proteins on AML blasts has been recognized as an important immune escape mechanism (29).…”

Section: Current Treatment Strategies In Acute Myeloid Leukemiamentioning

confidence: 99%

“…Today it is widely known that the structure and the function of BMM is altered to facilitate AML progression, dissemination and escape immune surveillance (202). Manipulation of the CXCL12/CXCR4 pathway is the key player in AML blasts' growth, survival, and chemotherapy resistance: CXCR4 expression on AML blasts that is involved in trafficking of malignant LSCs within BM while the migration of healthy stem cells in BM is prohibited (22). Regulation of tumor immune microenvironment stands out as a promising strategy in cancer treatment; in AML, inhibitors of several pathways are currently being investigated, either alone or in combination (203).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

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A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia

et al. 2023

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Acute myeloid leukemia (AML) arises from the cells of myeloid lineage and is the most frequent leukemia type in adulthood accounting for about 80% of all cases. The most common treatment strategy for the treatment of AML includes chemotherapy, in rare cases radiotherapy and stem cell and bone marrow transplantation are considered. Immune checkpoint proteins involve in the negative regulation of immune cells, leading to an escape from immune surveillance, in turn, causing failure of tumor cell elimination. Immune checkpoint inhibitors (ICIs) target the negative regulation of the immune cells and support the immune system in terms of anti-tumor immunity. Bone marrow microenvironment (BMM) bears various blood cell lineages and the interactions between these lineages and the noncellular components of BMM are considered important for AML development and progression. Administration of ICIs for the AML treatment may be a promising option by regulating BMM. In this review, we summarize the current treatment options in AML treatment and discuss the possible application of ICIs in AML treatment from the perspective of the regulation of BMM.

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“…To date, major efforts have been made to understand the immune landscape within the context of the bone marrow microenvironment in AML ( 15 , 16 ). However, the role of the thymic microenvironment in propagating AML progression is largely underrecognized, but a potentially important aspect of AML biology.…”

Section: Introductionmentioning

confidence: 99%

The potential role of the thymus in immunotherapies for acute myeloid leukemia

Hino

Xiao

et al. 2023

Front. Immunol.

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Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease’s progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).

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Targeting the Tumor Microenvironment in Acute Myeloid Leukemia: The Future of Immunotherapy and Natural Products

Cited by 12 publications

References 151 publications

Pan-cancer analysis reveals potential for synergy between SERPINA1 molecular targeting and macrophage-related immunotherapy

Pan-cancer analysis reveals potential for synergy between SERPINA1 molecular targeting and macrophage-related immunotherapy

A potential area of use for immune checkpoint inhibitors: Targeting bone marrow microenvironment in acute myeloid leukemia

The potential role of the thymus in immunotherapies for acute myeloid leukemia

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