bims-flamet 2024-06-09 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2024–06–09
23 papers selected by
Peio Azcoaga, Biodonostia HRI

Comprehensive Approach to Cancer Immunotherapy - Simultaneous Targeting of Myeloid-derived Suppressor Cells and Cancer Cells with AFP Conjugates.
Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives.
Role of lipid metabolism in hepatocellular carcinoma.
Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy.
Unlocking the crucial role of cancer-associated fibroblasts in tumor metastasis: Mechanisms and therapeutic prospects.
Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.
Interaction between intestinal flora and gastric cancer in tumor microenvironment.
Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.
The Impact of High Intensity Focused Ultrasound (HIFU) on Tumor-Specific Immune Responses of Prostate Cancer.
Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.
Remodeling of tumor microenvironment by extracellular matrix protein 1a differentially regulates ovarian cancer metastasis.
HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer.
Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.
Dietary commensal wrestles iron from tumor microenvironment to activate antitumoral macrophages.
Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them.
Engineered T Cell Receptor for Cancer Immunotherapy.
USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.
Therapeutic implications of signaling pathways and tumor microenvironment interactions in esophageal cancer.
DNA sensing of dendritic cells in cancer immunotherapy.
The transcriptional landscape of cancer stem-like cell functionality in breast cancer.
A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.
Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.
PD-L1 at the crossroad between RNA metabolism and immunosuppression.

Crit Rev Oncol Hematol. 2024 Jun 02. pii: S1040-8428(24)00150-1. [Epub ahead of print] 104407

Comprehensive Approach to Cancer Immunotherapy - Simultaneous Targeting of Myeloid-derived Suppressor Cells and Cancer Cells with AFP Conjugates.

Vladimir N Pak, Igor A Sherman.

  The immune system plays a pivotal role in combating diseases, including cancer, with monocytes emerging as key regulators of immune response dynamics. This article describes a novel strategy for cancer treatment centered on depleting myeloid-derived suppressor cells (MDSCs), to enhance the overall immune response while simultaneously targeting cancer cells directly. Alpha-fetoprotein (AFP) is an oncofetal protein that plays an important role in delivering nutrients to immature monocytes, embryonic, and cancer cells in a targeted manner. AFP can be repurposed, making it a vehicle for delivering toxins, rather than nutrients to kill cancer cells and deplete MDSCs in the tumor microenvironment (TME). Depleting monocytes not only stimulates the immune system but also improves the lymphocyte-to-monocyte ratio (LMR), often low in cancer patients. AFP combined with cytotoxic drugs, offers dual benefit-immune stimulation and targeted chemotherapy. Studies in xenograft models demonstrated high efficacy and safety of AFP-toxin conjugates, surpassing conventional targeted chemotherapy. Such conjugates have also been reported to provide superior efficacy and safety in cancer patients compared to chemotherapy. This approach, using AFP conjugated with toxins, either covalently or non-covalently, presents a safe and highly effective option for cancer immuno/chemotherapy.

Keywords:  AFP/AFP receptors; LMR; MDSCs; TME; immunotherapy; targeted chemotherapy

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104407
Front Immunol. 2024 ;15 1388176

Immunocytes interact directly with cancer cells in the tumor microenvironment: one coin with two sides and future perspectives.

Zhiyi Ye, Pu Cheng, Qi Huang, Jingjing Hu, Liming Huang, Guoming Hu.

  The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Keywords:  cancer cells; direct and dual effect; immunocytes; solid tumor; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1388176
Discov Oncol. 2024 Jun 04. 15(1): 206

Role of lipid metabolism in hepatocellular carcinoma.

Yulin Cheng, Jun He, Bin Zuo, Yang He.

  Hepatocellular carcinoma (HCC), an aggressive malignancy with a dismal prognosis, poses a significant public health challenge. Recent research has highlighted the crucial role of lipid metabolism in HCC development, with enhanced lipid synthesis and uptake contributing to the rapid proliferation and tumorigenesis of cancer cells. Lipids, primarily synthesized and utilized in the liver, play a critical role in the pathological progression of various cancers, particularly HCC. Cancer cells undergo metabolic reprogramming, an essential adaptation to the tumor microenvironment (TME), with fatty acid metabolism emerging as a key player in this process. This review delves into intricate interplay between HCC and lipid metabolism, focusing on four key areas: de novo lipogenesis, fatty acid oxidation, dysregulated lipid metabolism of immune cells in the TME, and therapeutic strategies targeting fatty acid metabolism for HCC treatment.

Keywords:  De novo lipogenesis; Fatty acid oxidation; Hepatocellular carcinoma; Lipid metabolism; Therapeutic strategy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s12672-024-01069-y
J Nanobiotechnology. 2024 Jun 08. 22(1): 319

Dual depletion of myeloid-derived suppressor cells and tumor cells with self-assembled gemcitabine-celecoxib nano-twin drug for cancer chemoimmunotherapy.

Xiaojie Zhang, Qiangwei Liang, Yongjin Cao, Ting Yang, Min An, Zihan Liu, Jiayu Yang, Yanhua Liu.

  Myeloid-derived suppressor cells (MDSCs) have played a significant role in facilitating tumor immune escape and inducing an immunosuppressive tumor microenvironment. Eliminating MDSCs and tumor cells remains a major challenge in cancer immunotherapy. A novel approach has been developed using gemcitabine-celecoxib twin drug-based nano-assembled carrier-free nanoparticles (GEM-CXB NPs) for dual depletion of MDSCs and tumor cells in breast cancer chemoimmunotherapy. The GEM-CXB NPs exhibit prolonged blood circulation, leading to the preferential accumulation and co-release of GEM and CXB in tumors. This promotes synergistic chemotherapeutic activity by the proliferation inhibition and apoptosis induction against 4T1 tumor cells. In addition, it enhances tumor immunogenicity by immunogenic cell death induction and MDSC-induced immunosuppression alleviation through the depletion of MDSCs. These mechanisms synergistically activate the antitumor immune function of cytotoxic T cells and natural killer cells, inhibit the proliferation of regulatory T cells, and promote the M2 to M1 phenotype repolarization of tumor-associated macrophages, considerably enhancing the overall antitumor and anti-metastasis efficacy in BALB/c mice bearing 4T1 tumors. The simplified engineering of GEM-CXB NPs, with their dual depletion strategy targeting immunosuppressive cells and tumor cells, represents an advanced concept in cancer chemoimmunotherapy.

Keywords:  Breast cancer; COX-2/PGE2 pathway; Chemoimmunotherapy; Gemcitabine-celecoxib; Myeloid-derived suppressor cells; Nano-twin drug

DOI:  https://doi.org/10.1186/s12951-024-02598-y
J Adv Res. 2024 May 31. pii: S2090-1232(24)00220-0. [Epub ahead of print]

Unlocking the crucial role of cancer-associated fibroblasts in tumor metastasis: Mechanisms and therapeutic prospects.

Yingxue Liu, Xiaoyan Zhang, Wenchao Gu, Hui Su, Xin Wang, Xu Wang, Jiayu Zhang, Midie Xu, Weiqi Sheng.

   BACKGROUND: Tumor metastasis represents a stepwise progression and stands as a principal determinant of unfavorable prognoses among cancer patients. Consequently, an in-depth exploration of its mechanisms holds paramount clinical significance. Cancer-associated fibroblasts (CAFs), constituting the most abundant stromal cell population within the tumor microenvironment (TME), have garnered robust evidence support for their pivotal regulatory roles in tumor metastasis.
AIM OF REVIEW: This review systematically explores the roles of CAFs at eight critical stages of tumorigenic dissemination: 1) extracellular matrix (ECM) remodeling, 2) epithelial-mesenchymal transition (EMT), 3) angiogenesis, 4) tumor metabolism, 5) perivascular migration, 6) immune escape, 7) dormancy, and 8) premetastatic niche (PMN) formation. Additionally, we provide a compendium of extant strategies aimed at targeting CAFs in cancer therapy.
KEY SCIENTIFIC CONCEPTS OF REVIEW: This review delineates a structured framework for the interplay between CAFs and tumor metastasis while furnishing insights for the potential therapeutic developments. It contributes to a deeper understanding of cancer metastasis within the TME, facilitating the utilization of CAF-targeting therapies in anti-metastatic approaches.

Keywords:  Cancer-associated fibroblasts; Metastasis; Therapy; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.jare.2024.05.031
Nat Cancer. 2024 Jun 03.

Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment.

Kevin M Tharp, Kelly Kersten, Ori Maller, Greg A Timblin, Connor Stashko, Fernando P Canale, Rosa E Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna Ten Hoeve, Bushra Samad, Alastrair J Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J Combes, Valerie M Weaver.

Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies.

DOI: https://doi.org/10.1038/s43018-024-00775-4
Front Oncol. 2024 ;14 1402483

Interaction between intestinal flora and gastric cancer in tumor microenvironment.

Mingjin Yang.

  Gastric Cancer (GC) is a prevalent malignancy globally and is the third leading cause of cancer-related deaths. Recent researches focused on the correlation between intestinal flora and GC. Studies indicate that bacteria can influence the development of gastrointestinal tumors by releasing bacterial extracellular vesicles (BEVs). The Tumor microenvironment (TME) plays an important role in tumor survival, with the interaction between intestinal flora, BEVs, and TME directly impacting tumor progression. Moreover, recent studies have demonstrated that intestinal microflora and BEVs can modify TME to enhance the effectiveness of antitumor drugs. This review article provides an overview and comparison of the biological targets through which the intestinal microbiome regulates TME, laying the groundwork for potential applications in tumor diagnosis, treatment, and prognosis.

Keywords:  antitumor drugs; bacterial extracellular vesicle; cancer; gastric cancer; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2024.1402483
Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00172-4. [Epub ahead of print]36(6): 1320-1334.e9

Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells.

Jing-Lin Liu, Xu Xu, Youlutuziayi Rixiati, Chu-Yi Wang, Heng-Li Ni, Wen-Shu Chen, Hui-Min Gong, Zi-Long Zhang, Shi Li, Tong Shen, Jian-Ming Li.

  Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8+ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.

Keywords:  circadian clock; intestinal microbiota; metabolites; metastasis; myeloid-derived suppressor cells

DOI:  https://doi.org/10.1016/j.cmet.2024.04.019
Arch Esp Urol. 2024 May;77(4): 322-330

The Impact of High Intensity Focused Ultrasound (HIFU) on Tumor-Specific Immune Responses of Prostate Cancer.

Wei Chen, Lina He, Haoran Huang, Xiang Zeng, Guangqing Fu, Yi Liu, Yong Liang.

  High intensity focused ultrasound (HIFU), also referred to as focused ultrasound surgery (FUS), has garnered recent attention as a non-invasive therapeutic strategy for prostate cancer. It utilizes focused acoustic energy to achieve localized thermal ablation, while also potentially exerting immunomodulatory effects. This review aims to elucidate the mechanisms underlying how HIFU influences tumor-specific immune responses in prostate cancer. These mechanisms include the release of tumor-associated antigens and damage-associated molecular patterns, the activation of innate immune cells, the facilitation of antigen presentation to adaptive immune cells, the enhancement of activation and proliferation of tumor-specific cytotoxic T lymphocytes, and the attenuation of the immunosuppressive tumor microenvironment by reducing the activity of regulatory T cells and myeloid-derived suppressor cells. Both preclinical investigations and emerging clinical data in prostate cancer models highlight HIFU's potential to modulate the immune system, as evidenced by increased infiltration of effector immune cells, elevated levels of pro-inflammatory cytokines, and improved responsiveness to immune checkpoint inhibitors. HIFU induces immunogenic cell death, leading to the release of tumor antigens and danger signals that activate dendritic cells and facilitate cross-presentation to cytotoxic T cells. Additionally, FUS ablation reduces immunosuppressive cells and increases infiltration of CD8+ T cells into the tumor, reshaping the tumor microenvironment. By priming the immune system while overcoming immunosuppression, combining FUS with other immunotherapies like checkpoint inhibitors and cancer vaccines holds promise for synergistic anti-tumor effects. Despite challenges in optimizing parameters and identifying suitable patients, FUS represents a novel frontier by modulating the tumor microenvironment and enhancing anti-tumor immunity through a non-invasive approach.

Keywords:  anti-tumor immune responses; focused ultrasound surgery; high intensity focused ultrasound; immunomodulation; prostate cancer

DOI:  https://doi.org/10.56434/j.arch.esp.urol.20247704.44
Cancer Immunol Immunother. 2024 Jun 04. 73(8): 138

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy.

Shaoxian Wu, Hongwei Jiang, Zhang Fang, You Wu, Jing Jiao, Weiwei Fang, Yue Wu, Yanyan Lang, Ning Chen, Ziyang Zhong, Lujun Chen, Xiao Zheng, Binfeng Lu, Jingting Jiang.

  Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies-MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)-has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

Keywords:  Anti-tumor; Effector function; Interleukin-21; Microwave ablation

DOI:  https://doi.org/10.1007/s00262-024-03718-1
Cancer Lett. 2024 Jun 05. pii: S0304-3835(24)00416-6. [Epub ahead of print] 217022

Remodeling of tumor microenvironment by extracellular matrix protein 1a differentially regulates ovarian cancer metastasis.

Yinjue Yu, Cuiting Lyu, Xiaojing Li, Lina Yang, Jingshu Wang, Hui Li, Zhaochen Xin, Xinyi Xu, Chunxia Ren, Gong Yang.

  We previously reported that extracellular matrix protein 1 isoform a (ECM1a) promotes epithelial ovarian cancer (EOC) through autocrine signaling through binding to cell surface receptors αXβ2. However, the role of ECM1a as a secretory molecule in the tumor microenvironment is rarely reported. In this study, we constructed murine Ecm1-knockout mice and human ECM1a-knockin mice and further generated orthotopic or peritoneal xenograft tumor models to mimic the different metastatic stages of EOC. We show that ECM1a induces oncogenic metastasis of orthotopic xenograft tumors, but inhibits early-metastasis of peritoneal xenograft tumors. ECM1a remodels extracellular matrices (ECM) and promotes remote metastases by recruiting and transforming bone marrow mesenchymal stem cells (BMSCs) into platelet-derived growth factor receptor beta (PDGFRβ+) cancer-associated fibroblasts (CAFs) and facilitating the secretion of angiopoietin-like protein 2 (ANGPTL2). Competing with ECM1a, ANGPTL2 also binds to integrin αX through the P1/P2 peptides, resulting in negative effects on BMSC differentiation. Collectively, this study reveals the dual functions of ECM1a in remodeling of TME during tumor progression, emphasizing the complexity of EOC phenotypic heterogeneity and metastasis.

Keywords:  Angiopoietin-like protein 2 (ANGPTL2); Cancer associated fibroblasts (CAFs); Epithelial ovarian cancer (EOC); Extracellular matrix protein 1 (ECM1); Extracellular matrix remodeling (ECM remodeling)

DOI:  https://doi.org/10.1016/j.canlet.2024.217022
Oncoimmunology. 2024 ;13(1): 2364382

HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer.

Nicole Ramos Solis, Anthony Cannon, Tinslee Dilday, Melissa Abt, Adrian L Oblak, Adam C Soloff, Mark H Kaplan, Elizabeth S Yeh.

  Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.

Keywords:  Breast cancer; HUNK; IL-4; tumor associated macrophage

DOI:  https://doi.org/10.1080/2162402X.2024.2364382
ACS Nano. 2024 Jun 05.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Zixu Liu, Boyuan Liu, Yupeng Feng, Linxuan Zhao, Qingqing Wang, Haibing He, Tian Yin, Yu Zhang, Li Yang, Jingxin Gou, Xing Tang.

  Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

Keywords:  STAT3 siRNA; STING pathway; dual-targeted; immune checkpoint blockade; nanovaccines; tumor-associated neutrophils

DOI:  https://doi.org/10.1021/acsnano.4c00392
Cancer Res. 2024 Jun 04.

Dietary commensal wrestles iron from tumor microenvironment to activate antitumoral macrophages.

Amanda H Lee, Simran K Randhawa, Marlies Meisel.

The microbiome dictates the response to cancer immunotherapy efficacy. However, the mechanisms of how the microbiota impacts on therapy efficacy remains still poorly understood. In a recent issue of Nature Immunology, Sharma and colleagues elucidate a multifaceted, macrophage-driven mechanism exerted by a specific strain of fermented food commensal Lactiplantibacillus plantarum, LpIMB19. LpIMB19 activates tumor macrophages, resulting in the enhancement of cytotoxic CD8 T cells. LpIMB19 administration led to an expansion of tumor-infiltrating CD8 T cells and improved the efficacy of anti-PD-L1 therapy. Rhamnose-rich heteropolysaccharide (RHP), a strain-specific cell wall component, was identified as the primary effector molecule of LplMB19. TLR2 signaling and the ability of macrophages to sequester iron were both critical for RHP-mediated macrophage activation upstream of the CD8 T cell effector response and contributed to tumor cell apoptosis through iron deprivation of tumor cells. These findings reveal a well-defined mechanism connecting diet and health outcomes, suggesting that diet-derived commensals may warrant further investigation. Additionally, this work emphasizes the importance of strain-specific differences in studying microbiome-cancer interactions and the concept of "nutritional immunity" to enhance microbe-triggered antitumor immunity.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1833
Cancer Drug Resist. 2024 ;7 18

Advancing CAR T-cell therapy for chronic lymphocytic leukemia: exploring resistance mechanisms and the innovative strategies to overcome them.

Azra Borogovac, Tanya Siddiqi.

  Chimeric antigen receptor (CAR) T-cell therapy has ushered in substantial advancements in the management of various B-cell malignancies. However, its integration into chronic lymphocytic leukemia (CLL) treatment has been challenging, attributed largely to the development of very effective chemo-free alternatives. Additionally, CAR T-cell responses in CLL have not been as high as in other B-cell lymphomas or leukemias. However, a critical void exists in therapeutic options for patients with high-risk diseases who are resistant to the current CLL therapies, underscoring the urgency for adoptive immunotherapies in these patients. The diminished CAR T-cell efficacy within CLL can be traced to factors such as compromised T-cell fitness due to persistent antigenic stimulation inherent to CLL. Resistance mechanisms encompass tumor-related factors like antigen escape, CAR T-cell-intrinsic factors like T-cell exhaustion, and a suppressive tumor microenvironment (TME). New strategies to combat CAR T-cell resistance include the concurrent administration of therapies that augment CAR T-cell endurance and function, as well as the engineering of novel CAR T-cells targeting different antigens. Moreover, the concept of "armored" CAR T-cells, armed with transgenic modulators to modify both CAR T-cell function and the tumor milieu, is gaining traction. Beyond this, the development of readily available, allogeneic CAR T-cells and natural killer (NK) cells presents a promising countermeasure to innate T-cell defects in CLL patients. In this review, we explore the role of CAR T-cell therapy in CLL, the intricate tapestry of resistance mechanisms, and the pioneering methods studied to overcome resistance.

Keywords:  CAR T-cells; CLL; allogeneic CART; resistance mechanisms

DOI:  https://doi.org/10.20517/cdr.2023.100
Biomol Ther (Seoul). 2024 Jun 07.

Engineered T Cell Receptor for Cancer Immunotherapy.

So Won Lee, Hyang-Mi Lee.

  Among therapeutic strategies in cancer immunotherapy, involving immune-modulating antibodies, cancer vaccine or adoptive T cell transfer, T cells has been attractive target due to their cytotoxicity toward tumor cells and tumor antigen-specific binding of receptors. Taking advantage of exclusive properties of T cells, chimeric antigen receptor (CAR)-T and T cell receptor (TCR)-T cells were generated by genetic edition of their receptors, which led an improvement in specificity and effectiveness of the T cell therapy. Adoptive cell transfer of CAR-T cells has been successful for the treatment of hematological malignancies. To expand T cell therapy to solid tumors, T cells are modified to express defined TCR targeting tumor associated antigen (TAA), which is called TCR-T therapy. Here in, this review discusses anti-tumor T cell therapies with focus on engineered TCR-T cell therapy. We describe features of TCR-T cell therapy, and clinical application of TCR-T cell therapy to non-hematological malignancies.

Keywords:  CAR-T cell; Cancer immunotherapy; Solid tumor; TCR-T cell

DOI:  https://doi.org/10.4062/biomolther.2023.197
Cancer Immunol Immunother. 2024 Jun 04. 73(8): 143

USP47 deficiency in mice modulates tumor infiltrating immune cells and enhances antitumor immune responses in prostate cancer.

Qian-Lan Wang, Shun-Yuan Lu, Dan-Dan Xu, Jin-Xia Ma, Rui Guo, Lu Zhang, Ling-Yun Tang, Yan Shen, Chun-Ling Shen, Jin-Jin Wang, Ying-Li Wu, Li-Ming Lu, Zhu-Gang Wang, Hong-Xin Zhang.

  This study investigates the role of USP47, a deubiquitinating enzyme, in the tumor microenvironment and its impact on antitumor immune responses. Analysis of TCGA database revealed distinct expression patterns of USP47 in various tumor tissues and normal tissues. Prostate adenocarcinoma showed significant downregulation of USP47 compared to normal tissue. Correlation analysis demonstrated a positive association between USP47 expression levels and infiltrating CD8+ T cells, neutrophils, and macrophages, while showing a negative correlation with NKT cells. Furthermore, using Usp47 knockout mice, we observed a slower tumor growth rate and reduced tumor burden. The absence of USP47 led to increased infiltration of immune cells, including neutrophils, macrophages, NK cells, NKT cells, and T cells. Additionally, USP47 deficiency resulted in enhanced activation of cytotoxic T lymphocytes (CTLs) and altered T cell subsets within the tumor microenvironment. These findings suggest that USP47 plays a critical role in modulating the tumor microenvironment and promoting antitumor immune responses, highlighting its potential as a therapeutic target in prostate cancer.

Keywords:  CTL; TIL; Tumor microenvironment; USP47

DOI:  https://doi.org/10.1007/s00262-024-03730-5
Biomed Pharmacother. 2024 Jun 05. pii: S0753-3322(24)00757-1. [Epub ahead of print]176 116873

Therapeutic implications of signaling pathways and tumor microenvironment interactions in esophageal cancer.

Inamu Rashid Khan, Hana Q Sadida, Sheema Hashem, Mayank Singh, Muzafar A Macha, Ammira S Al-Shabeeb Akil, Ibraq Khurshid, Ajaz A Bhat.

  Esophageal cancer (EC) is significantly influenced by the tumor microenvironment (TME) and altered signaling pathways. Downregulating these pathways in EC is essential for suppressing tumor development, preventing metastasis, and enhancing therapeutic outcomes. This approach can increase tumor sensitivity to treatments, enhance patient outcomes, and inhibit cancer cell proliferation and spread. The TME, comprising cellular and non-cellular elements surrounding the tumor, significantly influences EC's development, course, and treatment responsiveness. Understanding the complex relationships within the TME is crucial for developing successful EC treatments. Immunotherapy is a vital TME treatment for EC. However, the heterogeneity within the TME limits the application of anticancer drugs outside clinical settings. Therefore, identifying reliable microenvironmental biomarkers that can detect therapeutic responses before initiating therapy is crucial. Combining approaches focusing on EC signaling pathways with TME can enhance treatment outcomes. This integrated strategy aims to interfere with essential signaling pathways promoting cancer spread while disrupting factors encouraging tumor development. Unraveling aberrant signaling pathways and TME components can lead to more focused and efficient treatment approaches, identifying specific cellular targets for treatments. Targeting the TME and signaling pathways may reduce metastasis risk by interfering with mechanisms facilitating cancer cell invasion and dissemination. In conclusion, this integrative strategy has significant potential for improving patient outcomes and advancing EC research and therapy. This review discusses the altered signaling pathways and TME in EC, focusing on potential future therapeutics.

Keywords:  Cancer; Drug; Esophagus; Metastasis; Resistance; Signaling; TME; Therapy

DOI:  https://doi.org/10.1016/j.biopha.2024.116873
Front Mol Biosci. 2024 ;11 1391046

DNA sensing of dendritic cells in cancer immunotherapy.

Wei Qian, Jun Ye, Sheng Xia.

  Dendritic cells (DCs) are involved in the initiation and maintenance of immune responses against malignant cells by recognizing conserved pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) through pattern recognition receptors (PRRs). According to recent studies, tumor cell-derived DNA molecules act as DAMPs and are recognized by DNA sensors in DCs. Once identified by sensors in DCs, these DNA molecules trigger multiple signaling cascades to promote various cytokines secretion, including type I IFN, and then to induce DCs mediated antitumor immunity. As one of the potential attractive strategies for cancer therapy, various agonists targeting DNA sensors are extensively explored including the combination with other cancer immunotherapies or the direct usage as major components of cancer vaccines. Moreover, this review highlights different mechanisms through which tumor-derived DNA initiates DCs activation and the mechanisms through which the tumor microenvironment regulates DNA sensing of DCs to promote tumor immune escape. The contributions of chemotherapy, radiotherapy, and checkpoint inhibitors in tumor therapy to the DNA sensing of DCs are also discussed. Finally, recent clinical progress in tumor therapy utilizing agonist-targeted DNA sensors is summarized. Indeed, understanding more about DNA sensing in DCs will help to understand more about tumor immunotherapy and improve the efficacy of DC-targeted treatment in cancer.

Keywords:  DNA sensor; STING; TLR9; cGAS; cancer immunotherapy; dendritic cell

DOI:  https://doi.org/10.3389/fmolb.2024.1391046
J Transl Med. 2024 Jun 03. 22(1): 530

The transcriptional landscape of cancer stem-like cell functionality in breast cancer.

Oana Baldasici, Olga Soritau, Andrei Roman, Carmen Lisencu, Simona Visan, Laura Maja, Bogdan Pop, Bogdan Fetica, Andrei Cismaru, Laurian Vlase, Loredana Balacescu, Ovidiu Balacescu, Aman Russom, Oana Tudoran.

BACKGROUND: Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression.
METHODS: In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors.
RESULTS: We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer.
CONCLUSION: These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.

DOI: https://doi.org/10.1186/s12967-024-05281-w
Mol Cancer. 2024 Jun 01. 23(1): 117

A new era of cancer immunotherapy: combining revolutionary technologies for enhanced CAR-M therapy.

Na Li, Shinan Geng, Zhen-Zhen Dong, Ying Jin, Hangjie Ying, Hung-Wing Li, Liyun Shi.

  Significant advancements have been made in the application of chimeric antigen receptor (CAR)-T treatment for blood cancers during the previous ten years. However, its effectiveness in treating solid tumors is still lacking, necessitating the exploration of alternative immunotherapies that can overcome the significant challenges faced by current CAR-T cells. CAR-based immunotherapy against solid tumors shows promise with the emergence of macrophages, which possess robust phagocytic abilities, antigen-presenting functions, and the ability to modify the tumor microenvironment and stimulate adaptive responses. This paper presents a thorough examination of the latest progress in CAR-M therapy, covering both basic scientific studies and clinical trials. This study examines the primary obstacles hindering the realization of the complete potential of CAR-M therapy, as well as the potential strategies that can be employed to overcome these hurdles. With the emergence of revolutionary technologies like in situ genetic modification, synthetic biology techniques, and biomaterial-supported gene transfer, which provide a wider array of resources for manipulating tumor-associated macrophages, we suggest that combining these advanced methods will result in the creation of a new era of CAR-M therapy that demonstrates improved efficacy, safety, and availability.

Keywords:  Biomaterial gene delivery; CAR-M therapy; Chimeric antigen receptor; Macrophage

DOI:  https://doi.org/10.1186/s12943-024-02032-9
Cancer Res. 2024 Jun 04. 84(11): 1834-1855

Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer.

Nadia Boufaied, Paolo Chetta, Tarek Hallal, Stefano Cacciatore, Daniela Lalli, Carole Luthold, Kevin Homsy, Eddie L Imada, Sudeepa Syamala, Cornelia Photopoulos, Anna Di Matteo, Anna de Polo, Alessandra Maria Storaci, Ying Huang, Francesca Giunchi, Patricia A Sheridan, Gregory Michelotti, Quang-De Nguyen, Xin Zhao, Yang Liu, Elai Davicioni, Daniel E Spratt, Simone Sabbioneda, Giovanni Maga, Lorelei A Mucci, Claudia Ghigna, Luigi Marchionni, Lisa M Butler, Leigh Ellis, François Bordeleau, Massimo Loda, Valentina Vaira, David P Labbé, Giorgia Zadra.

Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer.
SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0519
Trends Mol Med. 2024 May 31. pii: S1471-4914(24)00096-0. [Epub ahead of print]

PD-L1 at the crossroad between RNA metabolism and immunosuppression.

Axel Arthur, Sanae Nejmi, Don-Marc Franchini, Estelle Espinos, Stefania Millevoi.

  Programmed death ligand-1 (PD-L1) is a key component of tumor immunosuppression. The uneven therapeutic results of PD-L1 therapy have stimulated intensive studies to better understand the mechanisms underlying altered PD-L1 expression in cancer cells, and to determine whether, beyond its immune function, PD-L1 might have intracellular functions promoting tumor progression and resistance to treatments. In this Opinion, we focus on paradigmatic examples highlighting the central role of PD-L1 in post-transcriptional regulation, with PD-L1 being both a target and an effector of molecular mechanisms featured prominently in RNA research, such as RNA methylation, phase separation and RNA G-quadruplex structures, in order to highlight vulnerabilities on which future anti-PD-L1 therapies could be built.

Keywords:  PD-L1; immunosuppression; post-transcriptional control

DOI:  https://doi.org/10.1016/j.molmed.2024.04.008