Targeting TREM2 on Tumor Associated Macrophages Enhances Efficacious Immunotherapy

Abushawish, Marwan; Dash, Subhadra; Pollack, Joshua L.; Rudolph, Joshua; Canaday, Pamela S.; Lu, Erick; Jahchan, Nadine S.; Norng, Manith; Mankikar, Shilpa; Lee, Tian; Liu, Victoria L.; Du, Xiaoyan; Chen, Amanda; Mehta, Ranna; Palmer, Rachael; Juric, Vladislava; Liang, Linda; Reyno, Leonard; Krummel, Matthew F.; Streuli, Michel; Sriram, Venkataraman

doi:10.2139/ssrn.3787006

Cited by 12 publications

(10 citation statements)

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“…(Molgora et al, 2020) In murine tumor models, genetic ablation of TREM2 decreased the number of intra-tumoral immunosuppressive TAMs and noticeably improved the efficacy of an anti-PD-1 treatment. (Katzenelenbogen et al, 2020;Molgora et al, 2020;Binnewies et al, 2021) Furthermore, TREM2 + TAMs were described to co-express various factors that facilitate tumor immune evasion, such as Arg1, Gpnmb or Spp1. (Sharma et al, 2020;Lazaratos et al, 2022) Likewise, anti-inflammatory TREM2 + TAMs were reported in primary liver cancers of patients and in mouse models.…”

Section: Tams Directly Fuel a Tumor-promoting Inflammatory Responsementioning

confidence: 99%

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Kohlhepp

Liu

Tacke

et al. 2023

Front. Mol. Biosci.

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Chronic liver diseases from varying etiologies generally lead to liver fibrosis and cirrhosis. Among them, non-alcoholic fatty liver disease (NAFLD) affects roughly one-quarter of the world population, thus representing a major and increasing public health burden. Chronic hepatocyte injury, inflammation (non-alcoholic steatohepatitis, NASH) and liver fibrosis are recognized soils for primary liver cancer, particularly hepatocellular carcinoma (HCC), being the third most common cause for cancer-related deaths worldwide. Despite recent advances in liver disease understanding, therapeutic options on pre-malignant and malignant stages remain limited. Thus, there is an urgent need to identify targetable liver disease-driving mechanisms for the development of novel therapeutics. Monocytes and macrophages comprise a central, yet versatile component of the inflammatory response, fueling chronic liver disease initiation and progression. Recent proteomic and transcriptomic studies performed at singular cell levels revealed a previously overlooked diversity of macrophage subpopulations and functions. Indeed, liver macrophages that encompass liver resident macrophages (also named Kupffer cells) and monocyte-derived macrophages, can acquire a variety of phenotypes depending on microenvironmental cues, and thus exert manifold and sometimes contradictory functions. Those functions range from modulating and exacerbating tissue inflammation to promoting and exaggerating tissue repair mechanisms (i.e., parenchymal regeneration, cancer cell proliferation, angiogenesis, fibrosis). Due to these central functions, liver macrophages represent an attractive target for the treatment of liver diseases. In this review, we discuss the multifaceted and contrary roles of macrophages in chronic liver diseases, with a particular focus on NAFLD/NASH and HCC. Moreover, we discuss potential therapeutic approaches targeting liver macrophages.

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Section: Tams Directly Fuel a Tumor-promoting Inflammatory Responsementioning

confidence: 99%

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Kohlhepp

Liu

Tacke

et al. 2023

Front. Mol. Biosci.

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“…In addition, TREM2-expressing TAMs lead to T-cell exhaustion that can hamper the success of T lymphocyte-based adoptive cell therapies. Depletion of TREM2-expressing TAMs by mAbs was shown to have a robust anti-tumor response alone and in combination with anti-PD1 antibodies through enhanced CD8+ TILs infiltration and effector function in an orthotopic ovarian cancer mouse model [ 92 ]. In addition, in a recent study, macrophage depletion using the F4/80 antibody in elderly mice improved the IL-2/anti-CD40 treatment response and achieved up to 78% tumor regression compared to 38% tumor regression in the intact macrophages control and reduced age-related treatment-induced cachexia [ 93 ].…”

Section: Pro-tumorigenic Roles Of Tamsmentioning

confidence: 99%

“…These strategies include the depletion of TAMs, the blocking of monocyte recruitment, the reprogramming of TAMs into proinflammatory M1 macrophages, and the neutralization of their products [ 17 , 39 , 205 ]. Several antagonists that target TAMs have already been tested in various clinical trials, even though most TAM-targeting strategies are still in the preclinical stages [ 8 , 15 , 89 , 92 , 186 , 206 , 207 , 208 , 209 , 210 ]. There are still a lot of obstacles to overcome and many issues to be resolved before targeting TAMs becomes a reality.…”

Section: Challenges In Therapeutic Targeting Of Tamsmentioning

confidence: 99%

Macrophages as a Potential Immunotherapeutic Target in Solid Cancers

et al. 2022

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The revolution in cancer immunotherapy over the last few decades has resulted in a paradigm shift in the clinical care of cancer. Most of the cancer immunotherapeutic regimens approved so far have relied on modulating the adaptive immune system. In recent years, strategies and approaches targeting the components of innate immunity have become widely recognized for their efficacy in targeting solid cancers. Macrophages are effector cells of the innate immune system, which can play a crucial role in the generation of anti-tumor immunity through their ability to phagocytose cancer cells and present tumor antigens to the cells of adaptive immunity. However, the macrophages that are recruited to the tumor microenvironment predominantly play pro-tumorigenic roles. Several strategies targeting pro-tumorigenic functions and harnessing the anti-tumorigenic properties of macrophages have shown promising results in preclinical studies, and a few of them have also advanced to clinical trials. In this review, we present a comprehensive overview of the pathobiology of TAMs and their role in the progression of solid malignancies. We discuss various mechanisms through which TAMs promote tumor progression, such as inflammation, genomic instability, tumor growth, cancer stem cell formation, angiogenesis, EMT and metastasis, tissue remodeling, and immunosuppression, etc. In addition, we also discuss potential therapeutic strategies for targeting TAMs and explore how macrophages can be used as a tool for next-generation immunotherapy for the treatment of solid malignancies.

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“…TAMs have been reported related to tumor infiltrating lymphocytes (TILs) in situ. [53][54][55] Notably, M2-type TAMs inhibit the activation of TILs (CD8 + T cells, CD4 + T cells), while M1-type TAMs active TILs by secreting some inflammation cytokines. Accordingly, the RNS-based PDT mediated by the coassembled hydrogel may increase the activation of TILs by M1 polarization.…”

Section: Immunotherapy Activation By Tams Polarization Triggered By T...mentioning

confidence: 99%

Supramolecular Coassembled Peptide Hydrogels for Efficient Anticancer Therapy by RNS‐Based PDT and Immune Microenvironment Regulation

Wang

et al. 2022

Macromolecular Bioscience

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Photodynamic therapy (PDT) has attracted much attention in cancer treatment due to its tumor selectivity and noninvasive nature. Recent studies have demonstrated that PDT mediated reactive oxygen species (ROS) generation in tumor microenvironment (TME) synergistically improves the efficacy of immune checkpoint blockade (ICB) therapy. However, the instability and short half‐life of the ROS generated by PDT limit its clinical applications. Herein, a coassembled peptide hydrogel comprising two short peptides that contained the same assembly unit, Ce6‐KKFKFEFEF (KEF‐Ce6) and RRRRRRRR‐KFKFEFEF (KEF‐R8) is developed. When exposed to 635 nm laser irradiation, KEF‐Ce6 released ROS, while KEF‐R8 plays as nitric oxide (NO) donor. Subsequently, ROS reacts with NO to produce reactive nitrogen species (RNS). Both in vitro and in vivo experiments prove that converting ROS into more cytotoxic RNS caused intense cell death. Importantly, it is observed that tumor‐associated macrophages (TAMs) are polarized to proinflammatory types (M1‐type) by the RNS‐based PDT. The increase of M1 macrophages relieves the immunosuppressive situation in TME. Thus, when combined with αPD‐L1 treatment, the survival time of tumor‐bearing mice is prolonged. Overall, a simple yet efficient coassembled hydrogel that can cascade release ROS/NO/RNS and strengthen antitumor T cell responses to boost cancer immunotherapy by reprogramming TAMs is provided.

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Targeting TREM2 on Tumor Associated Macrophages Enhances Efficacious Immunotherapy

Cited by 12 publications

References 0 publications

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

The contradictory roles of macrophages in non-alcoholic fatty liver disease and primary liver cancer—Challenges and opportunities

Macrophages as a Potential Immunotherapeutic Target in Solid Cancers

Supramolecular Coassembled Peptide Hydrogels for Efficient Anticancer Therapy by RNS‐Based PDT and Immune Microenvironment Regulation

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