Therapeutic Targeting of the Tumor Microenvironment

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(4), P. 933 - 959

Published: April 1, 2021

Abstract Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due critical roles of TME regulating progression and modulating response standard-of-care therapies. Here, we summarize current knowledge regarding most advanced TME-directed therapies, which either been clinically approved or are currently being evaluated trials, including immunotherapies, antiangiogenic drugs, treatments directed against cancer-associated fibroblasts extracellular matrix. We also discuss some challenges associated with future perspectives this evolving field. Significance: This review provides comprehensive analysis therapies targeting TME, combining discussion underlying basic biology clinical evaluation different therapeutic approaches, highlighting perspectives.

Language: Английский

---

Clinical and therapeutic relevance of cancer-associated fibroblasts

Nature Reviews Clinical Oncology, Journal Year: 2021, Volume and Issue: 18(12), P. 792 - 804

Published: Sept. 6, 2021

Language: Английский

---

Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer

Nature, Journal Year: 2022, Volume and Issue: 611(7937), P. 810 - 817

Published: Nov. 16, 2022

Abstract The tumour-associated microbiota is an intrinsic component of the tumour microenvironment across human cancer types 1,2 . Intratumoral host–microbiota studies have so far largely relied on bulk tissue analysis 1–3 , which obscures spatial distribution and localized effect within tumours. Here, by applying in situ spatial-profiling technologies 4 single-cell RNA sequencing 5 to oral squamous cell carcinoma colorectal cancer, we reveal spatial, cellular molecular host–microbe interactions. We adapted 10x Visium transcriptomics determine identity location intratumoral microbial communities patient tissues. Using GeoMx digital profiling 6 show that bacterial populate microniches are less vascularized, highly immuno‑suppressive associated with malignant cells lower levels Ki-67 as compared bacteria-negative regions. developed a RNA-sequencing method name INVADEseq (invasion–adhesion-directed expression sequencing) and, this tumours, identify cell-associated bacteria host they interact, well uncovering alterations transcriptional pathways involved inflammation, metastasis, dormancy DNA repair. Through functional studies, infected invade their surrounding environment single recruit myeloid Collectively, our data not random; instead, it organized immune epithelial functions promote progression.

Language: Английский

---

Fibroblasts as immune regulators in infection, inflammation and cancer

Nature reviews. Immunology, Journal Year: 2021, Volume and Issue: 21(11), P. 704 - 717

Published: April 28, 2021

Language: Английский

---

Cancer-associated fibroblasts in the single-cell era

Nature Cancer, Journal Year: 2022, Volume and Issue: 3(7), P. 793 - 807

Published: July 26, 2022

Language: Английский

---

Deciphering breast cancer: from biology to the clinic

Cell, Journal Year: 2023, Volume and Issue: 186(8), P. 1708 - 1728

Published: March 16, 2023

Language: Английский

---

Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer

Cancer Cell, Journal Year: 2022, Volume and Issue: 40(6), P. 656 - 673.e7

Published: May 5, 2022

Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting function in regulating tumor immunity. Here, integrating multiple single-cell RNA-sequencing and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, cells form downregulating features gaining fibroblastic features, process induced interleukin-1 transforming growth factor β. directly ligate induce naive CD4+ T into regulatory (Tregs) an antigen-specific manner. Moreover, treatment with antibody targeting cell marker mesothelin can effectively inhibit to apCAF transition Treg formation apCAFs. Taken together, our study elucidates how may contribute immune evasion provides insight on strategies enhance therapy.

Language: Английский

---

Spatially confined sub-tumor microenvironments in pancreatic cancer

Cell, Journal Year: 2021, Volume and Issue: 184(22), P. 5577 - 5592.e18

Published: Oct. 1, 2021

Intratumoral heterogeneity is a critical frontier in understanding how the tumor microenvironment (TME) propels malignant progression. Here, we deconvolute human pancreatic TME through large-scale integration of histology-guided regional multiOMICs with clinical data and patient-derived preclinical models. We discover "subTMEs," histologically definable tissue states anchored fibroblast plasticity, relationships to immunity, subtypes, differentiation, treatment response. "Reactive" subTMEs rich complex but functionally coordinated communities were immune hot inhabited by aggressive cell phenotypes. The matrix-rich "deserted" harbored fewer activated fibroblasts tumor-suppressive features yet markedly chemoprotective enriched upon chemotherapy. SubTMEs originated differentiation trajectories, transitory notable both single-cell transcriptomics situ. intratumoral co-occurrence produced patient-specific phenotypic computationally predictable tightly linked biology. Therefore, within plentiful, notorious not random marks fundamental organizational units.

Language: Английский

---

Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(11)

Published: April 27, 2021

Cancer-associated fibroblasts (CAF) may exert tumor-promoting and tumor-suppressive functions, but the mechanisms underlying these opposing effects remain elusive. Here, we sought to understand potentially functions by interrogating functional relationships among CAF subtypes, their mediators, desmoplasia, tumor growth in a wide range of types metastasizing liver, most common organ site for metastasis. Depletion hepatic stellate cells (HSC), which represented main source mice patients our study, or depletion all decreased mortality desmoplastic colorectal pancreatic metastasis not nondesmoplastic metastatic tumors. Single-cell RNA-Seq conjunction with CellPhoneDB ligand-receptor analysis, as well studies immune cell–depleted HSC-selective knockout mice, uncovered direct CAF-tumor interactions mechanism, mediated myofibroblastic CAF–secreted (myCAF-secreted) hyaluronan inflammatory (iCAF-secreted) HGF. These were opposed myCAF-expressed type I collagen, suppressed mechanically restraining spread, overriding its own stiffness-induced mechanosignals. In summary, mechanical restriction collagen opposes overall CAF, thus providing mechanistic explanation dual cancer. Therapeutic targeting mediators while preserving convert from promoting restricting.

Language: Английский

---

Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: Oct. 6, 2020

Ovarian cancer is the most lethal gynecologic malignancy. Surgery and chemotherapy are primary treatments for ovarian cancer; however, patients often succumb to recurrence with chemotherapeutic resistance within several years after initial treatment. In past two decades, immunotherapy has rapidly developed revolutionize treatment of various types cancer. Despite fact that response rates among remain modest, immune checkpoint inhibitors (ICIs), chimeric antigen receptor (CAR)- TCR-engineered T cells developing. Therapeutic efficiency could be improved significantly if included as an adjuvant therapy, in combination chemotherapy, radiation anti-angiogenesis drugs, poly ADP ribose polymerase (PARPi). Newly technologies identify therapeutic targets, predict efficacy, screen potential provide neoadjuvant immunotherapy, utilize nanomedicine technology new opportunities have prolong patient survival. However, important issues may hinder efficacy such approaches, including hyperprogressive disease (HPD), immunotherapy-resistance, toxicity treatments, neurotoxicity, must taken into account addressed these therapies effective.

Language: Английский

---