bims-flamet 2024-01-14 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–01–14
thirty-two papers selected by
Peio Azcoaga, Biodonostia HRI

Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.
Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies.
Hypoxia and programmed cell death-ligand 1 expression in the tumor microenvironment: a review of the effects of hypoxia-induced factor-1 on immunotherapy.
Cancer-Associated Fibroblasts: Major Co-Conspirators in Tumor Development.
Mutual regulation of PD-L1 immunosuppression between tumor-associated macrophages and tumor cells: a critical role for exosomes.
Immunosurveillance encounters cancer metabolism.
TAMs and PD-1 Networking in Gastric Cancer: A Review of the Literature.
The Role of the Toll-like Receptor 2 and the cGAS-STING Pathways in Breast Cancer: Friends or Foes?
TME-Related Biomimetic Strategies Against Cancer.
From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy.
Prolyl isomerase Pin1 sculpts the immune microenvironment of colorectal cancer.
Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy.
Evolving CAR-T-Cell Therapy for Cancer Treatment: From Scientific Discovery to Cures.
Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.
Dawn era for revisited cancer therapy by innate immune system and immune checkpoint inhibitors.
Genetic mechanisms underlying tumor microenvironment composition and function in diffuse large B cell lymphoma.
Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage polarity and prognostic indicators.
The promising role of tumor-associated macrophages in the treatment of cancer.
Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways.
Tumor-associated neutrophils in pancreatic cancer progression and metastasis.
IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.
Extracellular vesicles released by cancer-associated fibroblast-induced myeloid-derived suppressor cells inhibit T-cell function.
5-Oxo-ETE/OXER1: A Link between Tumor Cells and Macrophages Leading to Regulation of Migration.
Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.
Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy.
Intratumoral Influenza Vaccine Administration Attenuates Breast Cancer Growth and Restructures the Tumor Microenvironment through Sialic Acid Binding of Vaccine Hemagglutinin.
The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of CholangioCarcinoma.
The next bastion to be conquered in immunotherapy: microsatellite stable colorectal cancer.
TonEBP expression is essential in the IL-1β-induced migration and invasion of human A549 lung cancer cells.
Nano formulated Resveratrol inhibits PD-L1 in oral cancer cells by deregulating the association between tumor associated macrophages and cancer associated fibroblasts through IL-6/JAK2/STAT3 signaling axis.
Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47.
Myeloid-derived suppressor cells in cancer and cancer therapy.

Biomark Res. 2024 Jan 07. 12(1): 1

Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities.

Yujing Qian, Yujia Yin, Xiaocui Zheng, Zhaoyuan Liu, Xipeng Wang.

  Tumor-associated macrophages (TAMs) are a heterogeneous population that play diverse functions in tumors. Their identity is determined not only by intrinsic factors, such as origins and transcription factors, but also by external signals from the tumor microenvironment (TME), such as inflammatory signals and metabolic reprogramming. Metabolic reprogramming has rendered TAM to exhibit a spectrum of activities ranging from pro-tumorigenic to anti-tumorigenic, closely associated with tumor progression and clinical prognosis. This review implicates the diversity of TAM phenotypes and functions, how this heterogeneity has been re-evaluated with the advent of single-cell technologies, and the impact of TME metabolic reprogramming on TAMs. We also review current therapies targeting TAM metabolism and offer new insights for TAM-dependent anti-tumor immunotherapy by focusing on the critical role of different metabolic programs in TAMs.

Keywords:  Immunotherapy; Metabolic reprogramming; Single-cell omics; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s40364-023-00549-7
J Biomed Sci. 2024 Jan 12. 31(1): 5

Immune evasion in cell-based immunotherapy: unraveling challenges and novel strategies.

Yan-Ruide Li, Tyler Halladay, Lili Yang.

  Cell-based immunotherapies (CBIs), notably exemplified by chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, have emerged as groundbreaking approaches for cancer therapy. Nevertheless, akin to various other therapeutic modalities, tumor cells employ counterstrategies to manifest immune evasion, thereby circumventing the impact of CBIs. This phenomenon is facilitated by an intricately immunosuppression entrenched within the tumor microenvironment (TME). Principal mechanisms underpinning tumor immune evasion from CBIs encompass loss of antigens, downregulation of antigen presentation, activation of immune checkpoint pathways, initiation of anti-apoptotic cascades, and induction of immune dysfunction and exhaustion. In this review, we delve into the intrinsic mechanisms underlying the capacity of tumor cells to resist CBIs and proffer prospective stratagems to navigate around these challenges.

Keywords:  CAR-engineered T (CAR-T) cell therapy; Cell-based immunotherapies (CBIs); Chimeric antigen receptor (CAR); Immune checkpoint proteins; Immune evasion; Tumor heterogeneity; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s12929-024-00998-8
Mol Biol Rep. 2024 Jan 06. 51(1): 88

Hypoxia and programmed cell death-ligand 1 expression in the tumor microenvironment: a review of the effects of hypoxia-induced factor-1 on immunotherapy.

Fateme Khani Chamani, Atefe Etebari, Mahsa Hajivalili, Nariman Mosaffa, Seyed Amir Jalali.

  One useful cancer treatment approach is activating the patient's immune response against the tumor. In this regard, immunotherapy (IT) based on immune checkpoint blockers (ICBs) has made great progress in the last two decades. Although ITs are considered a novel approach to cancer treatment and have had good results in preclinical studies, their clinical success has shown that only a small proportion of treated patients (about 20%) benefited from them. Moreover, in highly progressed tumors, almost no acceptable response could be expected. In this regard finding the key molecules that are the main players of tumor immunosuppression might be helpful in overcoming the possible burdens. Hypoxia is one of the main components of the tumor microenvironment (TME), which can create an immunosuppressive microenvironment in various ways. For example, hypoxia is one of the main factors of programmed cell death ligand-1 (PD-L1) upregulation in tumor-infiltrating Myeloid-Derived Suppressor Cells (MDSCs). Therefore, hypoxia can be targeted to increase the efficiency of Anti-PD-L1 IT and has become one of the important issues in cancer treatment strategy. In this review, we described the effect of hypoxia in the TME, on tumor progression and immune responses and the challenges created by it for IT.

Keywords:  Hypoxia; Immunotherapy; Programmed cell death Ligand-1; Tumor microenvironment

DOI:  https://doi.org/10.1007/s11033-023-08947-8
Cancers (Basel). 2024 Jan 02. pii: 211. [Epub ahead of print]16(1):

Cancer-Associated Fibroblasts: Major Co-Conspirators in Tumor Development.

Shubhangi Singh, Ajay P Singh, Ranjana Mitra.

The tumor microenvironment (TME) is a critical determinant of tumor progression, metastasis, and therapeutic outcomes [...].

DOI: https://doi.org/10.3390/cancers16010211
Cell Commun Signal. 2024 Jan 09. 22(1): 21

Mutual regulation of PD-L1 immunosuppression between tumor-associated macrophages and tumor cells: a critical role for exosomes.

Banglu Wang, Daoan Cheng, Danyu Ma, Rui Chen, Dong Li, Weiqing Zhao, Cheng Fang, Mei Ji.

  Tumor cells primarily employ the PD-1/PD-L1 pathway to thwart the anti-tumor capabilities of T lymphocytes, inducing immunosuppression. This occurs through the direct interaction of PD-L1 with PD-1 on T lymphocyte surfaces. Recent research focusing on the tumor microenvironment has illuminated the pivotal role of immune cells, particularly tumor-associated macrophages (TAMs), in facilitating PD-L1-mediated immunosuppression. Exosomes, characterized by their ability to convey information and be engulfed by cells, significantly contribute to promoting TAM involvement in establishing PD-L1-mediated immunosuppression within the tumor microenvironment. Exosomes, characterized by their ability to convey information and be engulfed by cells, significantly contribute to promoting TAM involvement in establishing PD-L1-mediated immunosuppression within the tumor microenvironment. In addition to receiving signals from tumor-derived exosomes that promote PD-L1 expression, TAMs also exert control over PD-L1 expression in tumor cells through the release of exosomes. This paper aims to summarize the mechanisms by which exosomes participate in this process, identify crucial factors that influence these mechanisms, and explore innovative strategies for inhibiting or reversing the tumor-promoting effects of TAMs by targeting exosomes.

Keywords:  Exosome; Immunosuppression; PD-L1; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12964-024-01473-5
EMBO Rep. 2024 Jan 12.

Immunosurveillance encounters cancer metabolism.

Yu-Ming Chuang, Sheue-Fen Tzeng, Ping-Chih Ho, Chin-Hsien Tsai.

  Tumor cells reprogram nutrient acquisition and metabolic pathways to meet their energetic, biosynthetic, and redox demands. Similarly, metabolic processes in immune cells support host immunity against cancer and determine differentiation and fate of leukocytes. Thus, metabolic deregulation and imbalance in immune cells within the tumor microenvironment have been reported to drive immune evasion and to compromise therapeutic outcomes. Interestingly, emerging evidence indicates that anti-tumor immunity could modulate tumor heterogeneity, aggressiveness, and metabolic reprogramming, suggesting that immunosurveillance can instruct cancer progression in multiple dimensions. This review summarizes our current understanding of how metabolic crosstalk within tumors affects immunogenicity of tumor cells and promotes cancer progression. Furthermore, we explain how defects in the metabolic cascade can contribute to developing dysfunctional immune responses against cancers and discuss the contribution of immunosurveillance to these defects as a feedback mechanism. Finally, we highlight ongoing clinical trials and new therapeutic strategies targeting cellular metabolism in cancer.

Keywords:  Cancer Evolution; Immunoediting; Immunometabolism

DOI:  https://doi.org/10.1038/s44319-023-00038-w
Cancers (Basel). 2023 Dec 30. pii: 196. [Epub ahead of print]16(1):

TAMs and PD-1 Networking in Gastric Cancer: A Review of the Literature.

Melina Yerolatsite, Nanteznta Torounidou, Aristeidis Gogadis, Fani Kapoulitsa, Panagiotis Ntellas, Evangeli Lampri, Maria Tolia, Anna Batistatou, Konstantinos Katsanos, Davide Mauri.

   BACKGROUND: Gastric cancer (GC) is one of the most common and aggressive types of cancer. Immune checkpoint inhibitors (ICIs) have proven effective in treating various types of cancer. The use of ICIs in GC patients is currently an area of ongoing research. The tumor microenvironment (TME) also seems to play a crucial role in cancer progression. Tumor-associated macrophages (TAMs) are the most abundant population in the TME. TAMs are capable of displaying programmed cell death protein 1 (PD-1) on their surface and can form a ligand with programmed death ligand 1 (PD-L1), which is found on the surface of cancer cells. Therefore, it is expected that TAMs may significantly influence the immune response related to immune checkpoint inhibitors (ICIs).
AIM OF THE STUDY: Understanding the role of TAMs and PD-1/PD-L1 networking in GC.
METHODS: A systematic review of published data was performed using MEDLINE (PubMed), Embase, and Cochrane databases. We retrieved articles investigating the co-existence of TAMs and PD-1 in GC and the prognosis of patients expressing high levels of PD-1+ TAMs.
RESULTS: Ten articles with a total of 2277 patients were included in the systematic review. The examined data suggest that the expression of PD-L1 has a positive correlation with the infiltration of TAMs and that patients who express high levels of PD-1+ TAMs may have a worse prognosis than those who express low levels of PD-1+ TAMs.
CONCLUSIONS: TAMs play a pivotal role in the regulation of PD-1/PD-L1 networking and the progression of GC cells. Nevertheless, additional studies are needed to better define the role of TAMs and PD-1/PD-L1 networking in GC.

Keywords:  PD-1/PD-L1; gastric cancer; immune checkpoint inhibitors (ICIs); tumor microenvironment (TME); tumor-associated macrophages (TAMs)

DOI:  https://doi.org/10.3390/cancers16010196
Int J Mol Sci. 2023 Dec 29. pii: 456. [Epub ahead of print]25(1):

The Role of the Toll-like Receptor 2 and the cGAS-STING Pathways in Breast Cancer: Friends or Foes?

Chiara Cossu, Antonino Di Lorenzo, Irene Fiorilla, Alberto Maria Todesco, Valentina Audrito, Laura Conti.

  Breast cancer stands as a primary malignancy among women, ranking second in global cancer-related deaths. Despite treatment advancements, many patients progress to metastatic stages, posing a significant therapeutic challenge. Current therapies primarily target cancer cells, overlooking their intricate interactions with the tumor microenvironment (TME) that fuel progression and treatment resistance. Dysregulated innate immunity in breast cancer triggers chronic inflammation, fostering cancer development and therapy resistance. Innate immune pattern recognition receptors (PRRs) have emerged as crucial regulators of the immune response as well as of several immune-mediated or cancer cell-intrinsic mechanisms that either inhibit or promote tumor progression. In particular, several studies showed that the Toll-like receptor 2 (TLR2) and the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathways play a central role in breast cancer progression. In this review, we present a comprehensive overview of the role of TLR2 and STING in breast cancer, and we explore the potential to target these PRRs for drug development. This information will significantly impact the scientific discussion on the use of PRR agonists or inhibitors in cancer therapy, opening up new and promising avenues for breast cancer treatment.

Keywords:  Toll-like receptor 2; breast cancer; cGAS/STING; chemoresistance; innate immunity; pattern recognition receptors

DOI:  https://doi.org/10.3390/ijms25010456
Int J Nanomedicine. 2024 ;19 109-135

TME-Related Biomimetic Strategies Against Cancer.

Cheng Peng, Yilin Xu, Jing Wu, Donghai Wu, Lili Zhou, Xinhua Xia.

  The tumor microenvironment (TME) plays an important role in various stages of tumor generation, metastasis, and evasion of immune monitoring and treatment. TME targeted therapy is based on TME components, related pathways or active molecules as therapeutic targets. Therefore, TME targeted therapy based on environmental differences between TME and normal cells has been widely studied. Biomimetic nanocarriers with low clearance, low immunogenicity, and high targeting have enormous potential in tumor treatment. This review introduces the composition and characteristics of TME, including cancer‑associated fibroblasts (CAFs), extracellular matrix (ECM), tumor blood vessels, non-tumor cells, and the latest research progress of biomimetic nanoparticles (NPs) based on TME. It also discusses the opportunities and challenges of clinical transformation of biomimetic nanoparticles.

Keywords:  biomimetic delivery system; cell membrane-coating; nanoparticles; tumor therapy

DOI:  https://doi.org/10.2147/IJN.S441135
Histochem Cell Biol. 2024 Jan 08.

From complexity to clarity: unravelling tumor heterogeneity through the lens of tumor microenvironment for innovative cancer therapy.

Sikiru O Imodoye, Kamoru A Adedokun, Ibrahim O Bello.

  Despite the tremendous clinical successes recorded in the landscape of cancer therapy, tumor heterogeneity remains a formidable challenge to successful cancer treatment. In recent years, the emergence of high-throughput technologies has advanced our understanding of the variables influencing tumor heterogeneity beyond intrinsic tumor characteristics. Emerging knowledge shows that drivers of tumor heterogeneity are not only intrinsic to cancer cells but can also emanate from their microenvironment, which significantly favors tumor progression and impairs therapeutic response. Although much has been explored to understand the fundamentals of the influence of innate tumor factors on cancer diversity, the roles of the tumor microenvironment (TME) are often undervalued. It is therefore imperative that a clear understanding of the interactions between the TME and other tumor intrinsic factors underlying the plastic molecular behaviors of cancers be identified to develop patient-specific treatment strategies. This review highlights the roles of the TME as an emerging factor in tumor heterogeneity. More particularly, we discuss the role of the TME in the context of tumor heterogeneity and explore the cutting-edge diagnostic and therapeutic approaches that could be used to resolve this recurring clinical conundrum. We conclude by speculating on exciting research questions that can advance our understanding of tumor heterogeneity with the goal of developing customized therapeutic solutions.

Keywords:  Cancer stem cells; Cancer therapy; Immunotherapy; Tumor heterogeneity; Tumor microenvironment; Tumor plasticity

DOI:  https://doi.org/10.1007/s00418-023-02258-6
Cell Signal. 2024 Jan 08. pii: S0898-6568(24)00009-3. [Epub ahead of print] 111041

Prolyl isomerase Pin1 sculpts the immune microenvironment of colorectal cancer.

Yang Li, Zhongnan Yuan, Linlin Wang, Jing Yang, Pei Pu, Yunting Le, XianWei Chen, Chongyang Wang, Yating Gao, Yi Liu, Jialin Wang, Xu Gao, Yanze Li, Hefei Wang, Chaoxia Zou.

  Pin1, a peptide prolyl cis-trans isomerase, is overexpressed and/or overactivated in many human malignancies. However, whether Pin1 regulates the immunosuppressive TME has not been well defined. In this study, we detected the effect of Pin1 on immune cells and immune checkpoint PD-L1 in the TME of CRC and explored the anti-tumor efficacy of Pin1 inhibitor ATRA combined with PD-1 antibody. We found that Pin1 facilitated the immunosuppressive TME by raising the proportion of myeloid-derived suppressor cells (MDSCs) and declining the percentage of CD8+ T cells and CD4+ T cells. Pin1 restrained PD-L1 protein expression in CRC cells and the effect was tempered by endoplasmic reticulum (ER) stress inducers. Mechanically, Pin1 overexpression decreased the stability of PD-L1 and promoted its degradation by mitigating ER stress. Silencing or inhibiting Pin1 promoted PD-L1 protein expression by inducing ER stress. Hence, Pin1 inhibitor ATRA enhanced the anti-tumor efficacy of PD-1 antibody in the CRC allograft by upregulating PD-L1. Our results reveal the critical and pleiotropic effects of Pin1 on managing the immune cells and immune checkpoint PD-L1 in the TME of CRC, providing a new promising candidate for combination with immunotherapy.

Keywords:  Colorectal cancer; ER stress; PD-L1; Pin1; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.cellsig.2024.111041
Oncol Res. 2023 ;32(1): 49-60

Opportunities and challenges of CD47-targeted therapy in cancer immunotherapy.

Qiuqiang Chen, Xuejun Guo, Wenxue Ma.

  Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment.

Keywords:  CAR T-cell therapy; CD47; CD47-targeted therapies; Cancer cell; Cancer immunotherapy; Cancer treatment outcomes; Checkpoint inhibitors; Immune evasion; Macrophage; Tumor microenvironment

DOI:  https://doi.org/10.32604/or.2023.042383
Cancers (Basel). 2023 Dec 20. pii: 39. [Epub ahead of print]16(1):

Evolving CAR-T-Cell Therapy for Cancer Treatment: From Scientific Discovery to Cures.

Avisek Majumder.

  In recent years, chimeric antigen receptor (CAR)-T-cell therapy has emerged as the most promising immunotherapy for cancer that typically uses patients' T cells and genetically engineered them to target cancer cells. Although recent improvements in CAR-T-cell therapy have shown remarkable success for treating hematological malignancies, the heterogeneity in tumor antigens and the immunosuppressive nature of the tumor microenvironment (TME) limits its efficacy in solid tumors. Despite the enormous efforts that have been made to make CAR-T-cell therapy more effective and have minimal side effects for treating hematological malignancies, more research needs to be conducted regarding its use in the clinic for treating various other types of cancer. The main concern for CAR-T-cell therapy is severe toxicities due to the cytokine release syndrome, whereas the other challenges are associated with complexity and immune-suppressing TME, tumor antigen heterogeneity, the difficulty of cell trafficking, CAR-T-cell exhaustion, and reduced cytotoxicity in the tumor site. This review discussed the latest discoveries in CAR-T-cell therapy strategies and combination therapies, as well as their effectiveness in different cancers. It also encompasses ongoing clinical trials; current challenges regarding the therapeutic use of CAR-T-cell therapy, especially for solid tumors; and evolving treatment strategies to improve the therapeutic application of CAR-T-cell therapy.

Keywords:  B-cell lymphoma; TCR-T-cell receptor; blood cancer; cancer treatment; checkpoint blockade; chimeric antigen receptor (CAR); combination therapy; cytokine release syndrome; hematological malignancies; immuno-oncology; immunomodulation; immunotherapy; solid tumor; tumor microenvironment (TME)

DOI:  https://doi.org/10.3390/cancers16010039
Cold Spring Harb Perspect Med. 2024 Jan 08. pii: a041411. [Epub ahead of print]

Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.

Kathleen M McAndrews, Krishnan K Mahadevan, Raghu Kalluri.

The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed. Genetically engineered mouse models have enabled comprehensive insight into the complex interactions within the TME ecosystem that regulate disease progression. Here, we review recent advances in mouse models that have been employed to understand how the TME regulates cancer initiation, progression, metastasis, and response to therapy.

DOI: https://doi.org/10.1101/cshperspect.a041411
Biochim Biophys Acta Mol Basis Dis. 2024 Jan 09. pii: S0925-4439(24)00004-8. [Epub ahead of print] 167019

Dawn era for revisited cancer therapy by innate immune system and immune checkpoint inhibitors.

Hee-Do Kim, Chia-Ying Yeh, Yu-Chan Chang, Cheorl-Ho Kim.

  Immunotherapy is a promising therapeutic strategy for cancer. However, it shows limited efficacy against certain tumor types. The activation of innate immunity can suppress tumors by mitigating inflammatory and malignant behaviors through immune surveillance. The tumor microenvironment, which is composed of immune cells and cancer cells, plays a crucial role in determining the outcomes of immunotherapy. Relying solely on immune checkpoint inhibitors is not an optimal approach. Instead, there is a need to consider the use of a combination of immune checkpoint inhibitors with other modulators of the innate immune system to improve the tumor microenvironment. This can be achieved through methods such as immune cell antigen presentation and recognition. In this review, we delve into the significance of innate immune cells in tumor regression, as well as the role of the interaction of tumor cells with innate immune cells in evading host immune surveillance. These findings pave the way for the next chapter in the field of immunotherapy.

Keywords:  Immune checkpoint inhibitors; Immunotherapy; Innate immune system; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbadis.2024.167019
Blood. 2024 Jan 11. pii: blood.2023021002. [Epub ahead of print]

Genetic mechanisms underlying tumor microenvironment composition and function in diffuse large B cell lymphoma.

Leandro Cerchietti.

Cells in the tumor microenvironment (TME) of diffuse large B-cell lymphoma (DLBCL) show enormous diversity and plasticity, with functions that can range from tumor-inhibitory to tumor-supportive. The patient's age, immune status, and DLBCL treatments are factors that contribute to the shaping of this TME, but evidence suggests that genetic factors arising principally in lymphoma cells themselves, are among the most important. Here we review the current understanding of the role of these genetic drivers of DLBCL in establishing and modulating the lymphoma microenvironment. A better understanding of the relationship between lymphoma genetic factors and TME biology should lead to better therapeutic interventions, especially immunotherapies.

DOI: https://doi.org/10.1182/blood.2023021002
Mol Cancer. 2024 Jan 13. 23(1): 13

Deciphering tumor microenvironment: CXCL9 and SPP1 as crucial determinants of tumor-associated macrophage polarity and prognostic indicators.

Xinming Su, Chenhao Liang, Ruixiu Chen, Shiwei Duan.

  The tumor microenvironment (TME) is an intricate system comprised of tumor cells and the surrounding cellular and non-cellular components, exerting a pivotal influence on the initiation and progression of tumors. Exhibiting dynamic and diverse compositions as well as functional states across various tumors and patients, a profound comprehension of its specific internal interactions is indispensable for formulating efficacious anti-cancer treatment strategies. Extensive interactions among various immune cell types within the TME are well-documented, with their phenotypes and abundances closely linked to clinical prognoses. TME research is progressing towards greater complexity and precision, yet, to date, no representative TME biomarkers suitable for clinical applications have been definitively identified and validated. In a recent study, the collaborative actions of CXCL9 and SPP1 (CXCL9:SPP1) were found to collectively dictate the polarity of tumor-associated macrophages (TAMs) within the TME, exerting profound effects on tumor progression and treatment responses. The mutually exclusive expression of CXCL9:SPP1 in the TME not only governs TAM polarity but also exhibits strong correlations with immune cell profiles, antitumor factors, and patient outcomes, significantly influencing prognosis. This article consolidates the significance and prospects of CXCL9:SPP1 as a novel indicator for tumor development and prognosis, while also proposing future research directions and addressing potential challenges in this promising field.

Keywords:  Biomarkers; CXCL9; Prognosis; SPP1; Tumor microenvironment; Tumor-associated macrophages

DOI:  https://doi.org/10.1186/s12943-023-01931-7
Drug Resist Updat. 2024 Jan 03. pii: S1368-7646(23)00124-3. [Epub ahead of print]73 101041

The promising role of tumor-associated macrophages in the treatment of cancer.

Hongbin Wang, Xueying Wang, Xin Zhang, Wanhai Xu.

  Macrophages are important components of the immune system. Mature macrophages can be recruited to tumor microenvironment that affect tumor cell proliferation, invasion and metastasis, extracellular matrix remodeling, immune suppression, as well as chemotherapy resistance. Classically activated type I macrophages (M1) exhibited marked tumor killing and phagocytosis. Therefore, using macrophages for adoptive cell therapy has attracted attention and become one of the most effective strategies for cancer treatment. Through cytokines and/or chemokines, macrophage can inhibit myeloid cells recruitment, and activate anti-tumor and immune killing functions. Applying macrophages for anti-tumor delivery is one of the most promising approaches for cancer therapy. This review article introduces the role of macrophages in tumor development and drug resistance, and the possible clinical application of targeting macrophages for overcoming drug resistance and enhancing cancer therapeutics, as well as its challenges.

Keywords:  Drug resistance; Immunotherapy; M1; M2; Polarization; Tumor-associated macrophages

DOI:  https://doi.org/10.1016/j.drup.2023.101041
Biomark Res. 2024 Jan 08. 12(1): 5

Deciphering the role of neddylation in tumor microenvironment modulation: common outcome of multiple signaling pathways.

Dequan Liu, Xiangyu Che, Guangzhen Wu.

  Neddylation is a post-translational modification process, similar to ubiquitination, that controls several biological processes. Notably, it is often aberrantly activated in neoplasms and plays a critical role in the intricate dynamics of the tumor microenvironment (TME). This regulatory influence of neddylation permeates extensively and profoundly within the TME, affecting the behavior of tumor cells, immune cells, angiogenesis, and the extracellular matrix. Usually, neddylation promotes tumor progression towards increased malignancy. In this review, we highlight the latest understanding of the intricate molecular mechanisms that target neddylation to modulate the TME by affecting various signaling pathways. There is emerging evidence that the targeted disruption of the neddylation modification process, specifically the inhibition of cullin-RING ligases (CRLs) functionality, presents a promising avenue for targeted therapy. MLN4924, a small-molecule inhibitor of the neddylation pathway, precisely targets the neural precursor cell-expressed developmentally downregulated protein 8 activating enzyme (NAE). In recent years, significant advancements have been made in the field of neddylation modification therapy, particularly the integration of MLN4924 with chemotherapy or targeted therapy. This combined approach has demonstrated notable success in the treatment of a variety of hematological and solid tumors. Here, we investigated the inhibitory effects of MLN4924 on neddylation and summarized the current therapeutic outcomes of MLN4924 against various tumors. In conclusion, this review provides a comprehensive, up-to-date, and thorough overview of neddylation modifications, and offers insight into the critical importance of this cellular process in tumorigenesis.

Keywords:  Clinical trials; MLN4924; NEDD8; Neddylation; Signaling pathway; TME

DOI:  https://doi.org/10.1186/s40364-023-00545-x
Am J Cancer Res. 2023 ;13(12): 6176-6189

Tumor-associated neutrophils in pancreatic cancer progression and metastasis.

Reegan Sturgeon, Paran Goel, Rakesh K Singh.

Pancreatic cancer (PC) remains a challenge to modern-day cancer therapeutics, with a dismal five-year survival rate of 12%. Due to the pancreas's location and desmoplasia surrounding it, patients receive late diagnoses and fail to respond to chemotherapy regimens. Tumor-promoting inflammation, one of the emerging hallmarks of cancer, contributes to tumor cells' survival and proliferation. This inflammation often results from infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME). Neutrophils, one of our body's most prominent immune cells, are essential in sustaining the inflammation observed in the TME. Recent reports demonstrate that neutrophils are complicit in cancer progression and metastasis. Additionally, abundant data suggest that tumor-associated neutrophils (TANs) could be considered as one of the emerging targets for multiple cancer types, including PC. This review will focus on the most recent updates regarding neutrophil recruitments and functions in the cancer microenvironment and the potential development of neutrophils-targeted putative therapeutic strategies in PC.

Keywords: Neutrophils; cancer progression; metastasis; neutrophil extracellular traps; neutrophil polarization
Oncogene. 2024 Jan 12.

IFI35 limits antitumor immunity in triple-negative breast cancer via CCL2 secretion.

Baojin Xu, Hefen Sun, Simeng Liu, Li Liao, Xiaoqing Song, Yi Wu, Yifeng Hou, Wei Jin.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis due to the lack of therapeutic targets. Although immunotherapy brings survival benefits to patients diagnosed with TNBC, it remains limited and treatment resistance is widespread. Here we demonstrate that IFI35 is highly expressed in tumor tissues and can be induced by Interferon-γ in a time-dependent and concentration-dependent manner in breast cancer cells. In xenograft models, we reveal that IFI35 dramatically increases myeloid-derived suppressor cells infiltration in tumors, along with depletion and anergy of CD8+T cells. IFI35 ablation leads to prolonged survival of the mice. Mechanistically, RNA-sequencing reveals that IFI35 promotes CCL2 secretion, resulting in the remodeling of TNBC immune microenvironment. Ablation of IFI35 promotes the infiltration of effector CD8+T cells, and thereby sensitizes TNBC to anti-PD-1 immunotherapy. Our data suggest that IFI35 limits antitumor immunity and may be expected to become a new immunotherapy target in TNBC.

DOI: https://doi.org/10.1038/s41388-023-02934-w
Oncoimmunology. 2024 ;13(1): 2300882

Extracellular vesicles released by cancer-associated fibroblast-induced myeloid-derived suppressor cells inhibit T-cell function.

Carlo P Ramil, Handan Xiang, Peng Zhang, Aileen Cronin, Lisia Cabral, Zhizhang Yin, Josephine Hai, Huijun Wang, Benjamin Ruprecht, Yanlin Jia, Dongyu Sun, Hongmin Chen, An Chi.

  Myeloid cells are known to play a crucial role in creating a tumor-promoting and immune suppressive microenvironment. Our previous study demonstrated that primary human monocytes can be polarized into immunosuppressive myeloid-derived suppressor cells (MDSCs) by cancer-associated fibroblasts (CAFs) in a 3D co-culture system. However, the molecular mechanisms underlying the immunosuppressive function of MDSCs, especially CAF-induced MDSCs, remain poorly understood. Using mass spectrometry-based proteomics, we compared cell surface protein changes among monocytes, in vitro differentiated CAF-induced MDSCs, M1/M2 macrophages, and dendritic cells, and identified an extracellular vesicle (EV)-mediated secretory phenotype of MDSCs. Functional assays using an MDSC/T-cell co-culture system revealed that blocking EV generation in CAF-induced MDSCs reversed their ability to suppress T-cell proliferation, while EVs isolated from CAF-induced MDSCs directly inhibited T-cell function. Furthermore, we identified fructose bisphosphatase 1 (FBP1) as a cargo protein that is highly enriched in EVs isolated from CAF-induced MDSCs, and pharmacological inhibition of FBP1 partially reversed the suppressive phenotype of MDSCs. Our findings provide valuable insights into the cell surface proteome of different monocyte-derived myeloid subsets and uncover a novel mechanism underlying the interplay between CAFs and myeloid cells in shaping a tumor-permissive microenvironment.

Keywords:  Cancer-associated fibroblasts (CAF); extracellular vesicles (EV); myeloid-derived suppressor cells (MDSC); proteomics

DOI:  https://doi.org/10.1080/2162402X.2023.2300882
Molecules. 2023 Dec 31. pii: 224. [Epub ahead of print]29(1):

5-Oxo-ETE/OXER1: A Link between Tumor Cells and Macrophages Leading to Regulation of Migration.

Konstantina Kalyvianaki, Evangelia Maria Salampasi, Elias N Katsoulieris, Eleni Boukla, Amalia P Vogiatzoglou, George Notas, Elias Castanas, Marilena Kampa.

  Chronic inflammation is an important factor in the development of cancer. Macrophages found in tumors, known as tumor associated macrophages (TAMs), are key players in this process, promoting tumor growth through humoral and cellular mechanisms. 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), an arachidonic acid metabolite, has been described to possess a potent chemoattractant activity for human white blood cells (WBCs). The biological actions of 5-oxo-ETE are mediated through the GPCR 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor (OXER1). In addition, we have previously reported OXER1 as one of the membrane androgen receptors with testosterone antagonizing 5-oxo-ETE's actions. OXER1 is highly expressed in inflammatory cells and many normal and cancer tissues and cells, including prostate and breast cancer, promoting cancer cell survival. In the present study we investigate the expression and role of OXER1 in WBCs, THP-1 monocytes, and THP-1 derived macrophages, as well as its possible role in the interaction between macrophages and cancer cells (DU-145 and T47D). We report that OXER1 is differentially expressed between WBCs and macrophages and that receptor expression is modified by LPS treatment. Our results show that testosterone and 5-oxo-ETE can act in an antagonistic way affecting Ca2+ movements, migration, and cytokines' expression in immune-related cells, in a differentiation-dependent manner. Finally, we report that 5-oxo-ETE, through OXER1, can attract macrophages to the tumor site while tumor cells' OXER1 activation in DU-145 prostate and T47D breast cancer cells, by macrophages, induces actin cytoskeletal changes and increases their migration.

Keywords:  5-oxo-ETE; OXER1; TME; androgens; macrophages; migration; prostate cancer

DOI:  https://doi.org/10.3390/molecules29010224
Nat Cancer. 2024 Jan 12.

Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial.

Stephen J Bagley, Zev A Binder, Lamia Lamrani, Eliana Marinari, Arati S Desai, MacLean P Nasrallah, Eileen Maloney, Steven Brem, Robert A Lustig, Goldie Kurtz, Michelle Alonso-Basanta, Pierre-Emmanuel Bonté, Christel Goudot, Wilfrid Richer, Eliane Piaggio, Shawn Kothari, Lea Guyonnet, Coralie L Guerin, Joshua J Waterfall, Suyash Mohan, Wei-Ting Hwang, Oliver Y Tang, Meghan Logun, Meghna Bhattacharyya, Kelly Markowitz, Devora Delman, Amy Marshall, E John Wherry, Sebastian Amigorena, Gregory L Beatty, Jennifer L Brogdon, Elizabeth Hexner, Denis Migliorini, Cecile Alanio, Donald M O'Rourke.

We previously showed that chimeric antigen receptor (CAR) T-cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces upregulation of programmed death-ligand 1 (PD-L1) in the tumor microenvironment (TME). Here we conducted a phase 1 trial (NCT03726515) of CAR T-EGFRvIII cells administered concomitantly with the anti-PD1 (aPD1) monoclonal antibody pembrolizumab in patients with newly diagnosed, EGFRvIII+ glioblastoma (GBM) (n = 7). The primary outcome was safety, and no dose-limiting toxicity was observed. Secondary outcomes included median progression-free survival (5.2 months; 90% confidence interval (CI), 2.9-6.0 months) and median overall survival (11.8 months; 90% CI, 9.2-14.2 months). In exploratory analyses, comparison of the TME in tumors harvested before versus after CAR + aPD1 administration demonstrated substantial evolution of the infiltrating myeloid and T cells, with more exhausted, regulatory, and interferon (IFN)-stimulated T cells at relapse. Our study suggests that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicates a need to consider alternative strategies.

DOI: https://doi.org/10.1038/s43018-023-00709-6
Int J Mol Sci. 2023 Dec 19. pii: 6. [Epub ahead of print]25(1):

Targeting Farnesoid X Receptor in Tumor and the Tumor Microenvironment: Implication for Therapy.

Miljana Nenkov, Yihui Shi, Yunxia Ma, Nikolaus Gaßler, Yuan Chen.

  The farnesoid-X receptor (FXR), a member of the nuclear hormone receptor superfamily, can be activated by bile acids (BAs). BAs binding to FXR activates BA signaling which is important for maintaining BA homeostasis. FXR is differentially expressed in human organs and exists in immune cells. The dysregulation of FXR is associated with a wide range of diseases including metabolic disorders, inflammatory diseases, immune disorders, and malignant neoplasm. Recent studies have demonstrated that FXR influences tumor cell progression and development through regulating oncogenic and tumor-suppressive pathways, and, moreover, it affects the tumor microenvironment (TME) by modulating TME components. These characteristics provide a new perspective on the FXR-targeted therapeutic strategy in cancer. In this review, we have summarized the recent research data on the functions of FXR in solid tumors and its influence on the TME, and discussed the mechanisms underlying the distinct function of FXR in various types of tumors. Additionally, the impacts on the TME by other BA receptors such as takeda G protein-coupled receptor 5 (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic receptors (CHRM2 and CHRM3), have been depicted. Finally, the effects of FXR agonists/antagonists in a combination therapy with PD1/PD-L1 immune checkpoint inhibitors and other anti-cancer drugs have been addressed.

Keywords:  FXR; TME; combination therapy; immunotherapy; tumor

DOI:  https://doi.org/10.3390/ijms25010006
Int J Mol Sci. 2023 Dec 22. pii: 225. [Epub ahead of print]25(1):

Intratumoral Influenza Vaccine Administration Attenuates Breast Cancer Growth and Restructures the Tumor Microenvironment through Sialic Acid Binding of Vaccine Hemagglutinin.

Preston Daniels, Stefanie Cassoday, Kajal Gupta, Eileena Giurini, Malia E Leifheit, Andrew Zloza, Amanda L Marzo.

  Breast cancer continues to have a high disease burden worldwide and presents an urgent need for novel therapeutic strategies to improve outcomes. The influenza vaccine offers a unique approach to enhance the anti-tumor immune response in patients with breast cancer. Our study explores the intratumoral use of the influenza vaccine in a triple-negative 4T1 mouse model of breast cancer. We show that the influenza vaccine attenuated tumor growth using a three-dose intratumoral regimen. More importantly, prior vaccination did not alter this improved anti-tumor response. Furthermore, we characterized the effect that the influenza vaccine has on the tumor microenvironment and the underlying mechanisms of action. We established that the vaccine facilitated favorable shifts in restructuring the tumor microenvironment. Additionally, we show that the vaccine's ability to bind sialic acid residues, which have been implicated in having oncogenic functions, emerged as a key mechanism of action. Influenza hemagglutinin demonstrated binding ability to breast cancer cells through sialic acid expression. When administered intratumorally, the influenza vaccine offers a promising therapeutic strategy for breast cancer patients by reshaping the tumor microenvironment and modestly suppressing tumor growth. Its interaction with sialic acids has implications for effective therapeutic application and future research.

Keywords:  breast cancer; hemagglutinin; immunotherapy; influenza vaccine; sialic acid; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25010225
Curr Cancer Drug Targets. 2024 Jan 11.

The Tumor Immune Microenvironment plays a Key Role in Driving the Progression of CholangioCarcinoma.

Ye Zhang, Hai-Jiao Yan, Jun Wu.

  Cholangiocarcinoma (CCA) is an epithelial cancer distinguished by bile duct cell differentiation and is also a fibroproliferative tumor. It is characterized by a dense mesenchyme and a complex tumor immune microenvironment (TME). The TME comprises both cellular and non-cellular components. The celluar component includes CCA cells, immune cells and mesenchymal cells represented by the cancer-associated fibroblasts (CAFs), while the non-cellular component is represented by mesenchymal elements such as the extracellular matrix (ECM). Recent studies have demonstrated the important role of the TME in the development, progression, and treatment resistance of CCA. These cell-associated prognostic markers as well as intercellular connections, may serve as potential therapeutic targets and could inspire new treatment approaches for CCA in the future. This paper aims to summarize the current understanding of CCA's immune microenvironment, focusing on immune cells, mesenchymal cells, ECM, intercellular interactions, and metabolism within the microenvironment.

Keywords:  cholangiocarcinoma; immune cells; mesenchymal cells; metabolism; prognostic markers; tumor immune microenvironment

DOI:  https://doi.org/10.2174/0115680096267791231115101107
Front Immunol. 2023 ;14 1298524

The next bastion to be conquered in immunotherapy: microsatellite stable colorectal cancer.

Kai Ding, Pei Mou, Zhe Wang, Shuqing Liu, JinPei Liu, Hao Lu, Ganjun Yu.

  Colorectal cancer (CRC) is the second leading cause of cancer-related deaths worldwide, and its incidence continues to rise, particularly in developing countries. The advent of immune checkpoint inhibitors (ICIs) has represented a significant advancement in CRC treatment. Deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) serves as a biomarker for immunotherapy, with dMMR/MSI-H CRC exhibiting significantly better response rates to immunotherapy compared to proficient mismatch repair (pMMR)or microsatellite stable (MSS) CRC. While some progress has been made in the treatment of pMMR/MSS CRC in recent years, it remains a challenging issue in clinical practice. The tumor microenvironment (TME) plays a crucial role not only in the development and progression of CRC but also in determining the response to immunotherapy. Understanding the characteristics of the TME in pMMR/MSS CRC could offer new insights to enhance the efficacy of immunotherapy. In this review, we provide an overview of the current research progress on the TME characteristics and advancements in immunotherapy for pMMR/MSS CRC.

Keywords:  colorectal cancer; immune checkpoint inhibitors; immunotherapy; microsatellite stability; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2023.1298524
Oncol Res. 2023 ;32(1): 151-161

TonEBP expression is essential in the IL-1β-induced migration and invasion of human A549 lung cancer cells.

Hee Ju Song, Taehee Kim, Han Na Choi, Soo Jin Kim, Sang DO Lee.

  Lung cancer has the highest mortality rate among all cancers, in part because it readily metastasizes. The tumor microenvironment, comprising blood vessels, fibroblasts, immune cells, and macrophages [including tumor-associated macrophages (TAMs)], is closely related to cancer cell growth, migration, and invasion. TAMs secrete several cytokines, including interleukin (IL)-1β, which participate in cancer migration and invasion. p21-activated kinase 1 (PAK1), an important signaling molecule, induces cell migration and invasion in several carcinomas. Tonicity-responsive enhancer-binding protein (TonEBP) is also known to participate in cancer cell growth, migration, and invasion. However, the mechanisms by which it increases lung cancer migration remain unclear. Therefore, in this study, we aimed to elucidate the mechanisms by which IL-1β and TonEBP affect lung cancer cell migration and invasion. We found that A549 cocultured-MΦ-secreted IL-1β induced A549 cell migration and invasion via the PAK1 pathway. TonEBP deficiency reduced A549 cell migration and invasion and increased responsiveness to IL-1β-induced migration and invasion. PAK1 phosphorylation, which was promoted by IL-1β, was reduced when TonEBP was depleted. These results suggest that TonEBP plays an important role in IL-1β induction and invasiveness of A549 cells via the PAK1 pathway. These findings could be valuable in identifying potential targets for lung cancer treatment.

Keywords:  IL-1β; Lung cancer; TonEBP; Tumor microenvironment; Tumor-associated macrophage

DOI:  https://doi.org/10.32604/or.2023.030690
J Nutr Biochem. 2024 Jan 05. pii: S0955-2863(24)00002-0. [Epub ahead of print] 109568

Nano formulated Resveratrol inhibits PD-L1 in oral cancer cells by deregulating the association between tumor associated macrophages and cancer associated fibroblasts through IL-6/JAK2/STAT3 signaling axis.

Rajalaxmi Pradhan, Subarno Paul, Sushree Subhadra Acharya, Saptarshi Sinha, Somya Ranjan Dash, Chanakya Nath Kundu.

  Tumor associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) in the tumor microenvironment secrete several cytokines, which involved in tumor initiation, progression, metastatic outgrowth and angiogenesis. However, the association between TAMs and CAFs in the context of tumor development remain unclear. Here, we studied the relationship between TAMs and CAFs along with the involvement of cytokines in the production of cancer-stem-like-cells (CSCs) in oral cancer cells and explored the potential anti-cancer effects of Nano-formulated Resveratrol (Res-NP) using an activated macrophage-M1 (AM-M1) and activated fibroblast cells as the model system. IL-6 secretion was found to be enhanced in the conditioned-medium (CM) when AM-M1 cells + CAFs-like cells were co-cultured together. CSCs-enriched population was developed after addition of CM of AM-M1 +CAFs in H-357 cells and patient-derived-primary-oral-cancer cells. AM-M1 cells+ CAFs-like cells secreted IL-6 enhanced CSCs growth, proliferation, metastasis, and angiogenesis. IL-6 was found to promote PD-L1 expression in CSCs-enriched cells via JAK2/STAT3 pathway, as evident from the enhanced expression of p-JAK2 and p-STAT3. Nevertheless, Res-NP inhibited CSCs proliferation and reduced the expression of metastatic and angiogenic markers, in ovo blood vascularization, NO production and MMPs expression. Res-NP delinked the association between AM-M1 and CAFs by blocking IL-6 production and also disrupted the potential connection between IL-6 and PD-L1 with considerable decrease in p-JAK2 and p-STAT3 expressions. IL-6 depletion inhibited stemness and angiogenesis in oral CSCs by downregulating PD-L1 via JAK2/STAT3 cascade. Similar observations were also observed in Res-NP treated xenograft mice. Thus, data demonstrate that CSCs growth is dependent on IL-6/PD-L1 axis. Res-NP deregulates the association between AM-M1 and CAFs along-with attenuates carcinogenesis in in vitro, in ovo, ex vivo and in vivo model systems by inhibiting PD-L1 via IL-6/JAK2/STAT3 axis.

Keywords:  Activated macrophages-M1 (AM-M1); Cancer associated fibroblasts (CAFs); Cancer stem cells (CSCs); Cytokines; Metastasis; Oral cancer; Resveratrol-nanoparticle

DOI:  https://doi.org/10.1016/j.jnutbio.2024.109568
Nat Cancer. 2024 Jan 10.

Sirpα on tumor-associated myeloid cells restrains antitumor immunity in colorectal cancer independent of its interaction with CD47.

Chunliu Huang, Xuefei Wang, Yingzhao Wang, Yongyi Feng, Xiumei Wang, Shan Chen, Peidong Yan, Jing Liao, Qi Zhang, Chengzhou Mao, Yang Li, Lixiang Wang, Xinyu Wang, Wei Yi, Weibin Cai, Shoudeng Chen, Ni Hong, Weiling He, Jun Chen, Wenfei Jin.

Immunosuppressive myeloid cells hinder immunotherapeutic efficacy in tumors, but the precise mechanisms remain undefined. Here, by performing single-cell RNA sequencing in colorectal cancer tissues, we found tumor-associated macrophages and granulocytic myeloid-derived suppressor cells increased most compared to their counterparts in normal tissue and displayed the highest immune-inhibitory signatures among all immunocytes. These cells exhibited significantly increased expression of immunoreceptor tyrosine-based inhibitory motif-bearing receptors, including SIRPA. Notably, Sirpa-/- mice were more resistant to tumor progression than wild-type mice. Moreover, Sirpα deficiency reprogramed the tumor microenvironment through expansion of TAM_Ccl8hi and gMDSC_H2-Q10hi subsets showing strong antitumor activity. Sirpa-/- macrophages presented strong phagocytosis and antigen presentation to enhance T cell activation and proliferation. Furthermore, Sirpa-/- macrophages facilitated T cell recruitment via Syk/Btk-dependent Ccl8 secretion. Therefore, Sirpα deficiency enhances innate and adaptive immune activation independent of expression of CD47 and Sirpα blockade could be a promising strategy to improve cancer immunotherapy efficacy.

DOI: https://doi.org/10.1038/s43018-023-00691-z
Nat Rev Clin Oncol. 2024 Jan 08.

Myeloid-derived suppressor cells in cancer and cancer therapy.

Samantha A Lasser, Feyza G Ozbay Kurt, Ihor Arkhypov, Jochen Utikal, Viktor Umansky.

Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.

DOI: https://doi.org/10.1038/s41571-023-00846-y