bims-flamet 2023-06-25 papers

bims-flamet

Biomed News

on Cytokines and immunometabolism in metastasis

Issue of 2023–06–25
23 papers selected by
Peio Azcoaga, Biodonostia HRI

Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy.
Cancer-associated fibroblasts: Mediators of head and neck tumor microenvironment remodeling.
Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts.
Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies.
Revolutionizing anti-tumor therapy: unleashing the potential of B cell-derived exosomes.
Editorial: Understanding the crosstalk between immune cells and the tumor microenvironment in cancer and its implications for immunotherapy.
Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy.
Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy.
CAR T Cell Therapy: Remedies of Current Challenges in Design, Injection, Infiltration and Working.
The effect of Fas/FasL pathway blocking on apoptosis and stemness within breast cancer tumor microenvironment (preclinical study).
YTHDF2/m6 A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs.
Discovery of a novel dual-targeting D-peptide to block CD24/Siglec-10 and PD-1/PD-L1 interaction and synergize with radiotherapy for cancer immunotherapy.
The present roles and future perspectives of Interleukin-6 in biliary tract cancer.
Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma.
Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices.
Crosstalk between myeloid and B cells shapes the distinct microenvironments of primary and secondary liver cancer.
ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway.
Interactions between MFAP5 + fibroblasts and tumor-infiltrating myeloid cells shape the malignant microenvironment of colorectal cancer.
Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1.
Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway.
CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity.
Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors.
IL8 derived from macrophages inhibits CD8+ T-cell function by downregulating TIM3 expression through IL8-CXCR2 axis in patients with advanced colorectal cancer.

Front Immunol. 2023 ;14 1186383

Cell metabolism-based optimization strategy of CAR-T cell function in cancer therapy.

Wenshuai Li, Xuanxuan Pan, Lirong Chen, Haoshu Cui, Shaocong Mo, Yida Pan, Yuru Shen, Menglin Shi, Jianlin Wu, Feifei Luo, Jie Liu, Na Li.

  Adoptive cell therapy (ACT) using chimeric antigen receptor (CAR)-modified T cells has revolutionized the field of immune-oncology, showing remarkable efficacy against hematological malignancies. However, its success in solid tumors is limited by factors such as easy recurrence and poor efficacy. The effector function and persistence of CAR-T cells are critical to the success of therapy and are modulated by metabolic and nutrient-sensing mechanisms. Moreover, the immunosuppressive tumor microenvironment (TME), characterized by acidity, hypoxia, nutrient depletion, and metabolite accumulation caused by the high metabolic demands of tumor cells, can lead to T cell "exhaustion" and compromise the efficacy of CAR-T cells. In this review, we outline the metabolic characteristics of T cells at different stages of differentiation and summarize how these metabolic programs may be disrupted in the TME. We also discuss potential metabolic approaches to improve the efficacy and persistence of CAR-T cells, providing a new strategy for the clinical application of CAR-T cell therapy.

Keywords:  CAR (chimeric antigen receptor) T cells; cancer therapy; cell metabolism; immunity therapy; optimization strategy

DOI:  https://doi.org/10.3389/fimmu.2023.1186383
Biochim Biophys Acta Rev Cancer. 2023 Jun 16. pii: S0304-419X(23)00089-6. [Epub ahead of print] 188940

Cancer-associated fibroblasts: Mediators of head and neck tumor microenvironment remodeling.

Martina Raudenska, Jan Balvan, Klara Hanelova, Maria Bugajova, Michal Masarik.

  Cancer-associated fibroblasts (CAFs) are involved in critical aspects of head and neck squamous cell carcinoma (HNSCC) pathogenesis, such as the formation of a tumor-permissive extracellular matrix structure, angiogenesis, or immune and metabolic reprogramming of the tumor microenvironment (TME), with implications for metastasis and resistance to radiotherapy and chemotherapy. The pleiotropic effect of CAFs in TME is likely to reflect the heterogeneity and plasticity of their population, with context-dependent effects on carcinogenesis. The specific properties of CAFs provide many targetable molecules that could play an important role in the future therapy of HNSCC. In this review article, we will focus on the role of CAFs in the TME of HNSCC tumors. We will also discuss clinically relevant agents targeting CAFs, their signals, and signaling pathways, which are activated by CAFs in cancer cells, with the potential for repurposing for HNSCC therapy.

Keywords:  Head and neck cancer; Resistance to therapy; Tumor microenvironment; cancer therapy; cancer-associated fibroblasts

DOI:  https://doi.org/10.1016/j.bbcan.2023.188940
Front Immunol. 2023 ;14 1194642

Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts.

Eleonora Timperi, Emanuela Romano.

  The tumor associated macrophages (TAM) represent one of most abundant subpopulations across several solid cancers and their number/frequency is associated with a poor clinical outcome. It has been clearly demonstrated that stromal cells, such as the cancer associated fibroblasts (CAFs), may orchestrate TAM recruitment, survival and reprogramming. Today, single cell-RNA sequencing (sc-RNA seq) technologies allowed a more granular knowledge about TAMs and CAFs phenotypical and functional programs. In this mini-review we discuss the recent discoveries in the sc-RNA seq field focusing on TAM and CAF identity and their crosstalk in the tumor microenvironment (TME) of solid cancers.

Keywords:  cancer associated fibroblasts (CAF); monocytes; single cell RNA analysis; solid tumors; tumor associated macrophages (TAM)

DOI:  https://doi.org/10.3389/fimmu.2023.1194642
Dev Cell. 2023 06 19. pii: S1534-5807(23)00243-5. [Epub ahead of print]58(12): 1007-1021

Reshaping of the tumor microenvironment by cellular senescence: An opportunity for senotherapies.

Mariantonietta D'Ambrosio, Jesús Gil.

  Cellular senescence is a stress response associated with aging and disease, including cancer. Senescent cells undergo a stable cell cycle arrest, undergo a change in morphology and metabolic reprogramming, and produce a bioactive secretome termed the senescence-associated secretory phenotype (SASP). In cancer, senescence is an important barrier to tumor progression. Induction of senescence in preneoplastic cells limits cancer initiation, and many cancer therapies act in part by inducing senescence in cancer cells. Paradoxically, senescent cells lingering in the tumor microenvironment (TME) can contribute to tumor progression, metastasis, and therapy resistance. In this review, we discuss the different types of senescent cells present in the TME and how these senescent cells and their SASP reshape the TME, affect immune responses, and influence cancer progression. Furthermore, we will highlight the importance of senotherapies, including senolytic drugs that eliminate senescent cells and impede tumor progression and metastasis by restoring anti-tumor immune responses and influencing the TME.

Keywords:  SASP; TME; cancer; senescence; senescence-associated secretory phenotype; senolytics; tumor microenvironment

DOI:  https://doi.org/10.1016/j.devcel.2023.05.010
Front Immunol. 2023 ;14 1188760

Revolutionizing anti-tumor therapy: unleashing the potential of B cell-derived exosomes.

Jingwen Xiong, Hao Chi, Guanhu Yang, Songyun Zhao, Jing Zhang, Lisa Jia Tran, Zhijia Xia, Fang Yang, Gang Tian.

  B cells occupy a vital role in the functioning of the immune system, working in tandem with T cells to either suppress or promote tumor growth within the tumor microenvironment(TME). In addition to direct cell-to-cell communication, B cells and other cells release exosomes, small membrane vesicles ranging in size from 30-150 nm, that facilitate intercellular signaling. Exosome research is an important development in cancer research, as they have been shown to carry various molecules such as major histocompatibility complex(MHC) molecules and integrins, which regulate the TME. Given the close association between TME and cancer development, targeting substances within the TME has emerged as a promising strategy for cancer therapy. This review aims to present a comprehensive overview of the contributions made by B cells and exosomes to the tumor microenvironment (TME). Additionally, we delve into the potential role of B cell-derived exosomes in the progression of cancer.

Keywords:  B cell; B cell-derived exosome; TME; anti-tumor; therapy

DOI:  https://doi.org/10.3389/fimmu.2023.1188760
Front Med (Lausanne). 2023 ;10 1202581

Editorial: Understanding the crosstalk between immune cells and the tumor microenvironment in cancer and its implications for immunotherapy.

Noha Mousaad Elemam, Iman Mamdouh Talaat, Reem Amr Assal, Rana A Youness.



Keywords:  breast cancer; cancer; colorectal cancer; immune cells; immunotherapy; lung cancer; prognosis; tumor microenvironment

DOI:  https://doi.org/10.3389/fmed.2023.1202581
CNS Neurosci Ther. 2023 Jun 21.

Oxidative stress in pituitary neuroendocrine tumors: Affecting the tumor microenvironment and becoming a new target for pituitary neuroendocrine tumor therapy.

Yuhang Zhou, Anke Zhang, Chaoyou Fang, Ling Yuan, Anwen Shao, Yuanzhi Xu, Danyang Zhou.

  Pituitary adenomas (PAs), or pituitary neuroendocrine tumors (PitNETs), are commonly found in the anterior pituitary gland. Although the majority of PitNETs are benign and stable, several tumors have malignant characteristics. The tumor microenvironment (TME) plays an important role in the process of tumorigenesis and is composed of several types of cells. Various cells in the TME are significantly affected by oxidative stress. It has been reported that immunotherapeutic strategies have good effects in several cancers. However, the clinical potential of immunotherapies in PitNETs has not yet been fully discussed. Oxidative stress can regulate PitNET cells and immune cells in the TME, thus affecting the immune status of the TME of PitNETs. Therefore, modulation of oxidative stress-regulated immune cells using a combination of several agents and the immune system to suppress PitNETs is a promising therapeutic direction. In this review, we systematically analyzed the oxidative stress process within PitNET cells and various immune cells to elucidate the potential value of immunotherapy.

Keywords:  immunotherapy; oxidative stress; pituitary adenoma; pituitary neuroendocrine tumors; tumor microenvironment

DOI:  https://doi.org/10.1111/cns.14315
Front Immunol. 2023 ;14 1208788

Targeting CD137 (4-1BB) towards improved safety and efficacy for cancer immunotherapy.

Guizhong Liu, Peter Luo.

  T cells play a critical role in antitumor immunity, where T cell activation is regulated by both inhibitory and costimulatory receptor signaling that fine-tune T cell activity during different stages of T cell immune responses. Currently, cancer immunotherapy by targeting inhibitory receptors such as CTLA-4 and PD-1/L1, and their combination by antagonist antibodies, has been well established. However, developing agonist antibodies that target costimulatory receptors such as CD28 and CD137/4-1BB has faced considerable challenges, including highly publicized adverse events. Intracellular costimulatory domains of CD28 and/or CD137/4-1BB are essential for the clinical benefits of FDA-approved chimeric antigen receptor T cell (CAR-T) therapies. The major challenge is how to decouple efficacy from toxicity by systemic immune activation. This review focuses on anti-CD137 agonist monoclonal antibodies with different IgG isotypes in clinical development. It discusses CD137 biology in the context of anti-CD137 agonist drug discovery, including the binding epitope selected for anti-CD137 agonist antibody in competition or not with CD137 ligand (CD137L), the IgG isotype of antibodies selected with an impact on crosslinking by Fc gamma receptors, and the conditional activation of anti-CD137 antibodies for safe and potent engagement with CD137 in the tumor microenvironment (TME). We discuss and compare the potential mechanisms/effects of different CD137 targeting strategies and agents under development and how rational combinations could enhance antitumor activities without amplifying the toxicity of these agonist antibodies.

Keywords:  CD137/4-1BB; FcγR mediated cross-linking; TNFR agonist; cancer immunotherapy; conditional activation; costimulatory receptor

DOI:  https://doi.org/10.3389/fimmu.2023.1208788
Drug Des Devel Ther. 2023 ;17 1783-1792

CAR T Cell Therapy: Remedies of Current Challenges in Design, Injection, Infiltration and Working.

Yuxuan Zhu, Jianguo Feng, Rongxue Wan, Wenhua Huang.

  Chimeric antigen receptor (CAR) T cell therapy, as an innovative immunotherapy, plays a huge role in current cancer therapy. Although CAR T cell therapy has demonstrated therapeutic effects in some subtypes of B cell leukemia or lymphoma, there are many challenges that limit the therapeutic efficacy of CAR T cells in solid tumors. And how to efficiently transport CAR T cells to tumor tissues is a continuing concern for us. In this review, experiments have been extensively studied and compared. We finally compared the influence of different injection methods on therapeutic efficacy. We also carefully explored the difficulties of designing, homing, and working of CAR T cells, and ultimately came up with better solutions for each process to help CAR T cells reach tumor tissue more efficiently and quickly. These results will have significant implications for guiding CAR T cell therapy in cancer treatment.

Keywords:  CAR T cells; immunotherapy; infiltration; metastasis; tumor microenvironment

DOI:  https://doi.org/10.2147/DDDT.S413348
Breast Dis. 2023 ;42(1): 163-176

The effect of Fas/FasL pathway blocking on apoptosis and stemness within breast cancer tumor microenvironment (preclinical study).

Seham Abou Shousha, Suzan Baheeg, Hossam Ghoneim, Malak Zoheir, Mahmoud Hemida, Yasmine Shahine.

  Evasion of the immune system is the tumor's key strategy for its maintenance and progression. Thus, targeting the tumor microenvironment (TME) is considered one of the most promising approaches for fighting cancer, where immune cells within the TME play a vital role in immune surveillance and cancer elimination.FasL is one of the most important death ligands expressed by tumor-infiltrating lymphocytes (TILs) and plays a vital role in eliminating Fas-expressing cancer cells via Fas/FasL pathway-induced apoptosis. However, tumor cells can express elevated levels of FasL inducing apoptosis to TILs. Fas/FasL expression is linked to the maintenance of cancer stem cells (CSCs) within the TME, contributing to tumor aggressiveness, metastasis, recurrence, and chemoresistance.This study is considered the first study designed to block the overexpressed FasL on the tumor cells within TME mimicking tissue culture system using rFas molecules and supplementing the Fas enriched tissue culture system with blocked Fas - peripheral blood mononuclear cells PBMCs (using anti-Fas mAb) to protect them from tumor counterattack and augment their ability to induce tumor cell apoptosis and stemness inhibition.A significantly increased level of apoptosis and decreased expression of CD 44 (CSCs marker) was observed within the east tumor tissue culture system enriched with Fas molecules and anti-Fas treated PBMCs and the one enriched with Fas molecules only compared to the breast tumor tissues cultured alone (p < 0.001). Accordingly, we can consider the current study as a promising proposed immunotherapeutic strategy for breast cancer.

Keywords:  Stem cells; apoptosis; breast cancer; cell therapy; immunotherapy; in vitro

DOI:  https://doi.org/10.3233/BD-220077
EMBO J. 2023 Jun 22. e113126

YTHDF2/m6 A/NF-κB axis controls anti-tumor immunity by regulating intratumoral Tregs.

Linda Zhang, Xiaoyang Dou, Zhong Zheng, Chang Ye, Thomas X Lu, Hua L Liang, Liangliang Wang, Ralph R Weichselbaum, Chuan He.

  N6 -methyladenosine (m6 A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of the m6 A reader YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that the loss of YTHDF2 in regulatory T (Treg) cells reduces tumor growth in mice. Deletion of Ythdf2 in Tregs does not affect peripheral immune homeostasis but leads to increased apoptosis and impaired suppressive function of Treg cells in the TME. Elevated tumor necrosis factor (TNF) signaling in the TME promotes YTHDF2 expression, which in turn regulates NF-κB signaling by accelerating the degradation of m6 A-modified transcripts that encode NF-κB-negative regulators. This TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a potential target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance anti-tumor immune response while avoiding Treg cells in the periphery to minimize undesired inflammations.

Keywords:  Anti-tumor immunity; Intratumoral Tregs; NF-κB regulation; YTHDF2; m6A

DOI:  https://doi.org/10.15252/embj.2022113126
J Immunother Cancer. 2023 Jun;pii: e007068. [Epub ahead of print]11(6):

Discovery of a novel dual-targeting D-peptide to block CD24/Siglec-10 and PD-1/PD-L1 interaction and synergize with radiotherapy for cancer immunotherapy.

Wenhui Shen, Peishang Shi, Qingyu Dong, Xiuman Zhou, Chunxia Chen, Xinghua Sui, Wentong Tian, Xueqin Zhu, Xiaoxi Wang, Shengzhe Jin, Yahong Wu, Guanyu Chen, Lu Qiu, Wenjie Zhai, Yanfeng Gao.

   BACKGROUND: Aside from immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1), intervention of CD47/Sirpα mediated 'don't eat me' signal between macrophage and tumor cell is considered as a promising therapeutic approach for cancer immunotherapy. Compared with CD47, the novel immune checkpoint CD24/Siglec-10 can also deliver 'don't eat me' signal and CD24 shows much lower expression level in normal tissue which might avoid unwanted side effects.
METHODS: Cell-based phage display biopanning and D-amino acid modification strategy were used to identify the CD24/Siglec-10 blocking peptide. Cell-based blocking assay and microscale thermophoresis assay were used to validate the blocking and binding activities of the peptide. Phagocytosis and co-culture assays were used to explore the in vitro function of the peptide. Flow cytometry was performed to assess the immune microenvironment after the peptide treatment in vivo.
RESULTS: A CD24/Siglec-10 blocking peptide (CSBP) with hydrolysis-resistant property was identified. Surprisingly, we found that CSBP could not only block the interaction of CD24/Siglec-10 but also PD-1/PD-L1. CSBP could induce the phagocytosis of tumor cell by both the macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs), which can further activate CD8+ T cells. Besides, combination of radiotherapy and CSBP synergistically reduced tumor growth and altered the tumor microenvironment in both anti-PD-1-responsive MC38 and anti-PD-1-resistant 4T1 tumor models.
CONCLUSIONS: In summary, this is the first CD24/Siglec-10 blocking peptide which blocked PD-1/PD-L1 interaction as well, functioned via enhancing the phagocytosis of tumor cells by macrophages and M-MDSCs, and elevating the activity of CD8+ T cells for cancer immunotherapy.

Keywords:  immunotherapy; macrophages; radiotherapy; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2023-007068
Cytokine. 2023 Jun 16. pii: S1043-4666(23)00149-7. [Epub ahead of print]169 156271

The present roles and future perspectives of Interleukin-6 in biliary tract cancer.

Meng Zhou, Ruisi Na, Shihui Lai, Ying Guo, Jiaqi Shi, Jianhua Nie, Shuyuan Zhang, Yuan Wang, Tongsen Zheng.

  Biliary tract cancer (BTC) is a highly malignant tumor that originates from bile duct epithelium and is categorized into intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA) and gallbladder cancer (GBC) according to the anatomic location. Inflammatory cytokines generated by chronic infection led to an inflammatory microenvironment which influences the carcinogenesis of BTC. Interleukin-6 (IL-6), a multifunctional cytokine secreted by kupffer cells, tumor-associated macrophages, cancer-associated fibroblasts (CAFs) and cancer cells, plays a central role in tumorigenesis, angiogenesis, proliferation, and metastasis in BTC. Besides, IL-6 serves as a clinical biomarker for diagnosis, prognosis, and monitoring for BTC. Moreover, preclinical evidence indicates that IL-6 antibodies could sensitize tumor immune checkpoint inhibitors (ICIs) by altering the number of infiltrating immune cells and regulating the expression of immune checkpoints in the tumor microenvironment (TME). Recently, IL-6 has been shown to induce programmed death ligand 1 (PD-L1) expression through the mTOR pathway in iCCA. However, the evidence is insufficient to conclude that IL-6 antibodies could boost the immune responses and potentially overcome the resistance to ICIs for BTC. Here, we systematically review the central role of IL-6 in BTC and summarize the potential mechanisms underlying the improved efficacy of treatments combining IL-6 antibodies with ICIs in tumors. Given this, a future direction is proposed for BTC to increase ICIs sensitivity by blocking IL-6 pathways.

Keywords:  IL-6; biliary tract cancer; immune checkpoint inhibitors; immunotherapy; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cyto.2023.156271
J Immunother Cancer. 2023 Jun;pii: e006609. [Epub ahead of print]11(6):

Organ-specific heterogeneity in tumor-infiltrating immune cells and cancer antigen expression in primary and autologous metastatic lung adenocarcinoma.

David Restle, Joseph Dux, Xiaoyu Li, Alexander J Byun, Jennie K Choe, Yan Li, Raj G Vaghjiani, Carlos Thomas, Kyohei Misawa, Kay See Tan, David R Jones, Navin K Chintala, Prasad S Adusumilli.

   BACKGROUND: Tumor immune microenvironment (TIME) and cancer antigen expression, key factors for the development of immunotherapies, are usually based on the data from primary tumors due to availability of tissue for analysis; data from metastatic sites and their concordance with primary tumor are lacking. Although of the same origin from primary tumor, organ-specific differences in the TIME in metastases may contribute to discordant responses to immune checkpoint inhibitor agents. In immunologically 'cold' tumors, cancer antigen-targeted chimeric antigen receptor (CAR) T-cell therapy can promote tumor-infiltrating lymphocytes; however, data on distribution and intensity of cancer antigen expression in primary tumor and matched metastases are unavailable.
METHODS: We performed a retrospective review of a prospectively maintained database of patients who had undergone curative resection of pathological stage I-III primary lung adenocarcinoma from January 1995 to December 2012 followed by metastatic recurrence and resection of metastatic tumor (n=87). We investigated the relationship between the primary tumor and metastasis TIME (ie, tumor-infiltrating lymphocytes, tumor-associated macrophages, and programmed death-ligand 1 (PD-L1)) and cancer antigen expression (ie, mesothelin, CA125, and CEACAM6) using multiplex immunofluorescence.
RESULTS: Brain metastases (n=36) were observed to have fewer tumor-infiltrating lymphocytes and greater PD-L1-negative tumor-associated macrophages compared with the primary tumor (p<0.0001); this relatively inhibitory TIME was not observed in other metastatic sites. In one in three patients, expression of PD-L1 is discordant between primary and metastases. Effector-to-suppressor (E:S) cell ratio, median effector cells (CD20+ and CD3+) to suppressor cells (CD68/CD163+) ratio, in metastases was not significantly different between patients with varying E:S ratios in primary tumors. Cancer antigen distribution was comparable between primary and metastases; among patients with mesothelin, cancer antigen 125, or carcinoembryonic antigen adhesion molecule 6 expression in the primary tumor, the majority (51%-75%) had antigen expression in the metastases; however, antigen-expression intensity was heterogenous.
CONCLUSIONS: In patients with lung adenocarcinoma, brain metastases, but not other sites of metastases, exhibited a relatively immune-suppressive TIME; this should be considered in the context of differential response to immunotherapy in brain metastases. Among patients with cancer antigen expression in the primary tumor, the majority had antigen expression in metastases; these data can inform the selection of antigen-targeted CARs to treat patients with metastatic lung adenocarcinoma.

Keywords:  antigens; lymphocytes, tumor-infiltrating; programmed cell death 1 receptor; receptors, chimeric antigen; tumor microenvironment

DOI:  https://doi.org/10.1136/jitc-2022-006609
bioRxiv. 2023 Jun 11. pii: 2023.06.09.544394. [Epub ahead of print]

Monocytes use protrusive forces to generate migration paths in viscoelastic collagen-based extracellular matrices.

Kolade Adebowale, Byunghang Ha, Aashrith Saraswathibhatla, Dhiraj Indana, Medeea C Popescu, Sally Demirdjian, Jin Yang, Michael C Bassik, Christian Franck, Paul L Bollyky, Ovijit Chaudhuri.

Circulating monocytes are recruited to the tumor microenvironment, where they can differentiate into macrophages that mediate tumor progression. To reach the tumor microenvironment, monocytes must first extravasate and migrate through the type-1 collagen rich stromal matrix. The viscoelastic stromal matrix around tumors not only stiffens relative to normal stromal matrix, but often exhibits enhanced viscous characteristics, as indicated by a higher loss tangent or faster stress relaxation rate. Here, we studied how changes in matrix stiffness and viscoelasticity, impact the three-dimensional migration of monocytes through stromal-like matrices. Interpenetrating networks of type-1 collagen and alginate, which enable independent tunability of stiffness and stress relaxation over physiologically relevant ranges, were used as confining matrices for three-dimensional culture of monocytes. Increased stiffness and faster stress relaxation independently enhanced the 3D migration of monocytes. Migrating monocytes have an ellipsoidal or rounded wedge-like morphology, reminiscent of amoeboid migration, with accumulation of actin at the trailing edge. Matrix adhesions and Rho-mediated contractility were dispensable for monocyte migration in 3D, but migration did require actin polymerization and myosin contractility. Mechanistic studies indicate that actin polymerization at the leading edge generates protrusive forces that open a path for the monocytes to migrate through in the confining viscoelastic matrices. Taken together, our findings implicate matrix stiffness and stress relaxation as key mediators of monocyte migration and reveal how monocytes use pushing forces at the leading edge mediated by actin polymerization to generate migration paths in confining viscoelastic matrices.
Significance Statement: Cell migration is essential for numerous biological processes in health and disease, including for immune cell trafficking. Monocyte immune cells migrate through extracellular matrix to the tumor microenvironment where they can play a role in regulating cancer progression. Increased extracellular matrix (ECM) stiffness and viscoelasticity have been implicated in cancer progression, but the impact of these changes in the ECM on monocyte migration remains unknown. Here, we find that increased ECM stiffness and viscoelasticity promote monocyte migration. Interestingly, we reveal a previously undescribed adhesion-independent mode of migration whereby monocytes generate a path to migrate through pushing forces at the leading edge. These findings help elucidate how changes in the tumor microenvironment impact monocyte trafficking and thereby disease progression.

DOI: https://doi.org/10.1101/2023.06.09.544394
Cancer Res. 2023 Jun 23. pii: CAN-23-0193. [Epub ahead of print]

Crosstalk between myeloid and B cells shapes the distinct microenvironments of primary and secondary liver cancer.

Zhihang Chen, Guopei Zhang, Xiaoxue Ren, Zhijia Yao, Qian Zhou, Xuxin Ren, Shuling Chen, Lixia Xu, Kaiyu Sun, Qianwen Zeng, Ming Kuang, Dong-Ming Kuang, Sui Peng.

The tumor microenvironment is distinctive in primary and secondary liver cancer. B cells represent an important component of immune infiltrates. Here, we demonstrated that B cells are an important regulator in hepatocellular carcinoma (HCC) and colorectal cancer liver metastasis (CRLM) microenvironments. B cells displayed distinct developmental trajectories in HCC and CRLM. Single-cell analysis revealed that IgG+ plasma cells preferentially accumulated in HCC while IgA+ plasma cells were preferentially enriched in CRLM. Mechanistically, IgG+ plasma cells in HCC were recruited by tumor-associated macrophages via the CXCR3-CXCL10 axis, whereas IgA+ plasma cells in CRLM were recruited by metastatic tumor cells via CCR10-CCL28 signaling. Functionally, IgG+ plasma cells preferentially promoted pro-tumorigenic macrophages formation in HCC, and IgA+ plasma cells preferentially induced granulocytic myeloid-derived suppressor cells activation in CRLM. Clinically, increased infiltration of IgG+ plasma cells and macrophages in HCC was correlated to worse survival, while increased intratumoral IgA+ plasma cells and neutrophils in CRLM indicated poor prognosis. Taken together, this study demonstrated plasma and myeloid cell-mediated immunosuppression in HCC and CRLM, suggesting that selectively modulating primary or secondary tumor-related immunosuppressive regulatory networks might reprogram the microenvironment and provide an immunotherapeutic strategy for treating liver cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-0193
bioRxiv. 2023 Jun 05. pii: 2023.06.01.543353. [Epub ahead of print]

ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway.

Songnan Wang, Volker Böhnert, Alby J Joseph, Valentino Sudaryo, Jason Swinderman, Feiqiao B Yu, Xuchao Lyu, Gemini Skariah, Vishvak Subramanyam, Luke A Gilbert, Hani Goodarzi, Lingyin Li.

ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 that restrains their response to tumor-derived cGAMP. Enpp1 loss-of-function in both cancer cells and normal tissues slowed primary tumor initiation and growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Strikingly, we find that breast cancer patients with low ENPP1 expression have significantly higher immune infiltration and improved response to therapeutics impacting cancer immunity upstream or downstream of the cGAMP-STING pathway, like PARP inhibitors and anti-PD1. Altogether, selective inhibition of ENPP1's cGAMP hydrolase activity alleviates an innate immune checkpoint to boost cancer immunity and is therefore a promising therapeutic approach against breast cancer that may synergize with other cancer immunotherapies.

DOI: https://doi.org/10.1101/2023.06.01.543353
J Transl Med. 2023 Jun 21. 21(1): 405

Interactions between MFAP5 + fibroblasts and tumor-infiltrating myeloid cells shape the malignant microenvironment of colorectal cancer.

Zhiwei Peng, Zihao Ren, Zhiwei Tong, Yinan Zhu, Yansong Zhu, Kongwang Hu.

   BACKGROUND: The therapeutic targeting of the tumor microenvironment (TME) in colorectal cancer (CRC) has not yet been fully developed and utilized because of the complexity of the cell-cell interactions within the TME. The further exploration of these interactions among tumor-specific clusters would provide more detailed information about these communication networks with potential curative value.
METHODS: Single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing datasets were integrated in this study to explore the biological properties of MFAP5 + fibroblasts and their interactions with tumor-infiltrating myeloid cells in colorectal cancer. Immunohistochemistry and multiplex immunohistochemistry were performed to confirm the results of these analyses.
RESULTS: We profiled heterogeneous single-cell landscapes across 27,414 cells obtained from tumors and adjacent tissues. We mainly focused on the pro-tumorigenic functions of the identified MFAP5 + fibroblasts. We demonstrated that tumor-resident MFAP5 + fibroblasts and myeloid cells (particularly C1QC + macrophages) were positively correlated in both spatial transcriptomics and bulk RNA-seq public cohorts. These cells and their interactions might shape the malignant behavior of CRC. Intercellular interaction analysis suggested that MFAP5 + fibroblasts could reciprocally communicate with C1QC + macrophages and other myeloid cells to remodel unfavorable conditions via MIF/CD74, IL34/CSF1R, and other tumor-promoting signaling pathways.
CONCLUSION: Our study has elucidated the underlying pro-tumor mechanisms of tumor-resident MFAP5 + fibroblasts and provided valuable targets for the disruption of their properties.

Keywords:  C1QC; Colorectal cancer; Fibroblasts; MFAP5; Macrophages; Single cell RNA-sequencing; Spatial transcriptomics

DOI:  https://doi.org/10.1186/s12967-023-04281-6
Oncoimmunology. 2023 ;12(1): 2223094

Reprogramming the immunosuppressive tumor microenvironment results in successful clearance of tumors resistant to radiation therapy and anti-PD-1/PD-L1.

Debayan Mukherjee, Erminia Romano, Richard Walshaw, Leo A H Zeef, Antonia Banyard, Stephen J Kitcatt, Eleanor J Cheadle, Karoliina Tuomela, Swati Pendharkar, Aws Al-Deka, Beatrice Salerno, Sophie Raby, Ian G Mills, Jamie Honeychurch, Tim M Illidge.

  Despite breakthroughs in immune checkpoint inhibitors (ICI), the majority of tumors, including those poorly infiltrated by CD8+ T cells or heavily infiltrated by immunosuppressive immune effector cells, are unlikely to result in clinically meaningful tumor responses. Radiation therapy (RT) has been combined with ICI to potentially overcome this resistance and improve response rates but reported clinical trial results have thus far been disappointing. Novel approaches are required to overcome this resistance and reprogram the immunosuppressive tumor microenvironment (TME) and address this major unmet clinical need. Using diverse preclinical tumor models of prostate and bladder cancer, including an autochthonous prostate tumor (Pten-/-/trp53-/-) that respond poorly to radiation therapy (RT) and anti-PD-L1 combinations, the key drivers of this resistance within the TME were profiled and used to develop rationalized combination therapies that simultaneously enhance activation of anti-cancer T cell responses and reprogram the immunosuppressive TME. The addition of anti-CD40mAb to RT resulted in an increase in IFN-y signaling, activation of Th-1 pathways with an increased infiltration of CD8+ T-cells and regulatory T-cells with associated activation of the CTLA-4 signaling pathway in the TME. Anti-CTLA-4mAb in combination with RT further reprogrammed the immunosuppressive TME, resulting in durable, long-term tumor control. Our data provide novel insights into the underlying mechanisms of the immunosuppressive TME that result in resistance to RT and anti-PD-1 inhibitors and inform therapeutic approaches to reprogramming the immune contexture in the TME to potentially improve tumor responses and clinical outcomes.

Keywords:  Radiotherapy; Tregs; immune Checkpoints; immunotherapy

DOI:  https://doi.org/10.1080/2162402X.2023.2223094
Thorac Cancer. 2023 Jun 21.

Lactate secreted by esophageal cancer cells induces M2 macrophage polarization via the AKT/ERK pathway.

Chunsheng Zhang, Wei Cheng, Tongjin Yang, Hanlin Fang, Renquan Zhang.

   BACKGROUND: Elevated lactate results in an acidic tumor microenvironment (TME), which stimulates the progression of esophageal cancer (EC). Tumor-associated macrophages (TAMs) are an essential component of the TME. However, the regulatory mechanisms of lactate secreted by EC on TAMs and the effects of EC advancement are unclear.
METHODS: Proteins and mRNA expression were determined by western blot and RT-qPCR. Cell metastasis and growth were assessed by scratch assay, transwell and BrdU assays. Lactate in cells was quantified using a lactate kit. A mouse model was constructed for validation in vivo.
RESULTS: First, we determined that lactate upgraded the M2-type polarization marker levels of macrophages. Cell function assays confirmed that lactate-activated M2 macrophages accelerated EC cell migration and proliferation in vitro. However, the lactate inhibitor - oxamate hampered the level of lactate in TE-1 cells. Oxamate abolished the facilitation of macrophage polarization by lactate. In addition, we discovered that phosphorylated AKT and phosphorylated ERK was obviously raised in lactate-stimulated macrophages, and oxamate addition reversed this change, implying that AKT and ERK signaling pathways were involved in macrophage polarization. Response experiments proved that attenuation of AKT/ERK signaling markedly returned the lactate-induced promotion of EC migration and proliferation by macrophages. Finally, mouse tumor models demonstrated that lactate enhanced EC growth by inducing M2 macrophage polarization.
CONCLUSION: EC-secreted lactate stimulated macrophage M2 polarization via the AKT/ERK pathway thereby boosting the growth of EC.

Keywords:  AKT; EC; ERK; M2 macrophages; lactate

DOI:  https://doi.org/10.1111/1759-7714.14998
Res Sq. 2023 Jun 06. pii: rs.3.rs-2972427. [Epub ahead of print]

CAR T-cell design dependent remodeling of the brain tumor immune microenvironment identify macrophages as key players that inhibit or promote anti-tumor activity.

Dalia Haydar, Jorge Ibañez-Vega, Jeremy Crawford, Ching-Heng Chou, Cliff Guy, Michaela Meehl, Zhongzhen Yi, Deanna Langfitt, Peter Vogel, Christopher DeRenzo, Stephen Gottschalk, Martine Roussel, Paul Thomas, Giedre Krenciute.

Understanding interactions between adoptively transferred immune cells and the tumor immune microenvironment (TIME) is critical for developing successful T-cell based immunotherapies. Here we investigated the impact of the TIME and chimeric antigen receptor (CAR) design on anti-glioma activity of B7-H3-specific CAR T-cells. We show that five out of six B7-H3 CARs with varying transmembrane, co-stimulatory, and activation domains, exhibit robust functionality in vitro . However, in an immunocompetent glioma model, these CAR T-cells demonstrated significantly varied levels of anti-tumor activity. We used single-cell RNA sequencing to examine the brain TIME after CAR T-cell therapy. We show that the TIME composition was influenced by CAR T-cell treatment. We also found that successful anti-tumor responses were supported by the presence and activity of macrophages and endogenous T-cells. Together, our study demonstrates that efficacy of CAR T-cell therapy in high-grade glioma is dependent on CAR structural design and its capacity to modulate the TIME.

DOI: https://doi.org/10.21203/rs.3.rs-2972427/v1
Hematol Oncol Clin North Am. 2023 Jun 21. pii: S0889-8588(23)00064-3. [Epub ahead of print]

Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors.

Jeremiah A Wala, Glenn J Hanna.

  We review chimeric antigen receptor (CAR) T-cell therapy for solid tumors. We discuss patient selection factors and aspects of clinical management. We describe challenges including physical and molecular barriers to trafficking CAR-Ts, an immunosuppressive tumor microenvironment, and difficulty finding cell surface target antigens. The application of new approaches in synthetic biology and cellular engineering toward solid tumor CAR-Ts is described. Finally, we summarize reported and ongoing clinical trials of CAR-T therapies for select disease sites such as head and neck (including thyroid cancer), lung, central nervous system (glioblastoma, neuroblastoma, glioma), sarcoma, genitourinary (prostate, renal, bladder, kidney), breast and ovarian cancer.

Keywords:  Antigen selection; Cellular engineering; Chimeric antigen receptor; Clinical trials; Solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.hoc.2023.05.009
Int Immunopharmacol. 2023 Jun 16. pii: S1567-5769(23)00780-4. [Epub ahead of print]121 110457

IL8 derived from macrophages inhibits CD8+ T-cell function by downregulating TIM3 expression through IL8-CXCR2 axis in patients with advanced colorectal cancer.

Chenhui Zhao, Dan Wang, Zhen Li, Zhen Zhang, Yujie Xu, Jinbo Liu, Qingyang Lei, Dong Han, Yachang Huo, Shasha Liu, Ling Li, Yi Zhang.

   BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a vital immune checkpoint that regulates the immune response. However, the specific role of TIM3 in patients with colorectal cancer (CRC) have rarely been studied. In this study, we investigated the effect of TIM3 on CD8+ T cells in CRC and explored the mechanism of TIM3 regulation in tumor microenvironment (TME).
METHODS: Peripheral blood and tumor tissues of patients with CRC were collected to evaluate TIM3 expression using flow cytometry. Cytokines in the serum of healthy donors and patients with early- and advanced-stage CRC were screened using a multiplex assay. The effects of interleukin-8 (IL8) on TIM3 expression on CD8+ T cells were analyzed using cell incubation experiments in vitro. The correlation between TIM3 or IL8 and prognosis was verified using bioinformatics analysis.
RESULTS: TIM3 expression on CD8+ T cells was obviously reduced in patients with advanced-stage CRC, whereas a lower TIM3 expression level was associated with poorer prognosis. Macrophage-derived IL8, which could inhibit TIM3 expression on CD8+ T cells, was significantly increased in the serum of patients with advanced CRC. In addition, the function and proliferation of CD8+ and TIM3+CD8+ T cells were inhibited by IL8, which was partly depending on TIM3 expression. The inhibitory effects of IL8 were reversed by anti-IL8 and anti-CXCR2 antibodies.
CONCLUSIONS: In summary, macrophages-derived IL8 suppresses TIM3 expression on CD8+ T cells through CXCR2. Targeting the IL8/CXCR2 axis may be an effective strategy for treating patients with advanced CRC.

Keywords:  CD8(+) T cell; Colorectal carcer; IL8; TIM3; Tumor-associated macrophage

DOI:  https://doi.org/10.1016/j.intimp.2023.110457