Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

Johnson, Racheal; Cummings, Michele; Thangavelu, Amudha; Theophilou, Georgios; Jong, Diederick de; Orsi, Nicolas M.

doi:10.3390/cancers13246231

Cited by 16 publications

(17 citation statements)

References 344 publications

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“…14 15 The basis of ICI therapy failure in EOC involves multiple mechanisms, including low tumor mutational burden (TMB), abnormal neovascularization, altered metabolism, failure to reverse T cell exhaustion, and robust humoral and cellular immunosuppression in the TME. 16 The abundance and phenotype of different populations of myeloid cells, particularly TAMs, are critical determinants of the primary and adaptive resistance to ICIs in a broad range of solid tumors. 101 102 TAMs confer resistance through direct and indirect effects on T cell effector functions by altering the cytokine/chemokine milieu, as well as by upregulating coinhibitory molecules.…”

Section: Clinical Relevance Of Tams In Eoc Impact Of Tams On Eoc Prog...mentioning

confidence: 99%

“…14 15 The mechanisms of treatment failure in EOC are complex and involve genomic factors, altered metabolism, abnormal neovascularization and, most importantly, robust infiltration of immunosuppressive immune cells into the TME, particularly tumorassociated macrophages (TAMs). 16 Here, we review the clinical relevance of TAMs in EOC. We first discuss how the ovarian TME recruits TAMs and modulates their polarization, as well as the mechanisms by which TAMs contribute to the development and progression of EOC.…”

Section: Introductionmentioning

confidence: 99%

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Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Truxová

Cibula

Špíšek

et al. 2023

J Immunother Cancer

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Epithelial ovarian cancer (EOC) is among the top five causes of cancer-related death in women, largely reflecting early, prediagnosis dissemination of malignant cells to the peritoneum. Despite improvements in medical therapies, particularly with the implementation of novel drugs targeting homologous recombination deficiency, the survival rates of patients with EOC remain low. Unlike other neoplasms, EOC remains relatively insensitive to immune checkpoint inhibitors, which is correlated with a tumor microenvironment (TME) characterized by poor infiltration by immune cells and active immunosuppression dominated by immune components with tumor-promoting properties, especially tumor-associated macrophages (TAMs). In recent years, TAMs have attracted interest as potential therapeutic targets by seeking to reverse the immunosuppression in the TME and enhance the clinical efficacy of immunotherapy. Here, we review the key biological features of TAMs that affect tumor progression and their relevance as potential targets for treating EOC. We especially focus on the therapies that might modulate the recruitment, polarization, survival, and functional properties of TAMs in the TME of EOC that can be harnessed to develop superior combinatorial regimens with immunotherapy for the clinical care of patients with EOC.

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Section: Clinical Relevance Of Tams In Eoc Impact Of Tams On Eoc Prog...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Truxová

Cibula

Špíšek

et al. 2023

J Immunother Cancer

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“…Due to the complex interconnected signaling network and the unique peritoneal TME, cancer cells can interact with CAFs, adipocytes, immune cells, and chemokines (2). As a result, tumor migration and immune evasion frequently occur in OC patients, and immunotherapy has little effect (3).…”

Section: Introductionmentioning

confidence: 99%

Integrative Analysis From Multicenter Studies Identifies a WGCNA-Derived Cancer-Associated Fibroblast Signature for Ovarian Cancer

Feng

Dai

et al. 2022

Front. Immunol.

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Cancer-associated fibroblasts (CAFs) are a major contributor to tumor stromal crosstalk in the tumor microenvironment (TME) and boost tumor progression by promoting angiogenesis and lymphangiogenesis. This study aimed to identify prognostic genes associated with CAFs that lead to high morbidity and mortality in ovarian cancer (OC) patients. We performed bioinformatics analysis in 16 multicenter studies (2,742 patients) and identified CAF-associated hub genes using the weighted gene co-expression network analysis (WGCNA). A machine learning methodology was used to identify COL16A1, COL5A2, GREM1, LUM, SRPX, and TIMP3 and construct a prognostic signature. Subsequently, a series of bioinformatics algorithms indicated risk stratification based on the above signature, suggesting that high-risk patients have a worse prognosis, weaker immune response, and lower tumor mutational burden (TMB) status but may be more sensitive to routine chemotherapeutic agents. Finally, we characterized prognostic markers using cell lines, immunohistochemistry, and single-cell sequencing. In conclusion, these results suggest that the CAF-related signature may be a novel pretreatment guide for anti-CAFs, and prognostic markers in CAFs may be potential therapeutic targets to inhibit OC progression.

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“…Thus, ICIs have become a subject of several combinatorial regimens with various p53-specific targeted therapies. Examples include p53MVA [182], SGT-53 [183], Ad-p53 [184], Ad-p53 + CD122/132 [181], OBP-702 (a wild-type p53 expressing oncolytic adenovirus), CXCR4-targeted p53 mRNA nanoparticles [185], and APR-246 with anti-PD-1 in several cancer models. While most of these combinations have not been evaluated in breast cancers, the consensus from these studies is that these various combinations resulted in 1) increased immune response such as cytotoxic T cell activities and CD8+ T cell infiltration, 2) a reduction in immunosuppressive cells (M2 macrophages) and expression of immunosuppressive regulators, and 3) have the potential to reverse resistance to ICIs.…”

Section: Mutant P53 Immunotherapies and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

Marvalim¹,

Datta²,

Lee³

2023

Theranostics

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The transcription factor p53 is an important regulator of a multitude of cellular processes. In the presence of genotoxic stress, p53 is activated to facilitate DNA repair, cell cycle arrest, and apoptosis. In breast cancer, the tumor suppressive activities of p53 are frequently inactivated by either the overexpression of its negative regulator MDM2, or mutation which is present in 30-35% of all breast cancer cases. Notably, the frequency of p53 mutation is highly subtype dependent in breast cancers, with majority of hormone receptor-positive or luminal subtypes retaining the wild-type p53 status while hormone receptor-negative patients predominantly carry p53 mutations with gain-of-function oncogenic activities that contribute to poorer prognosis. Thus, a two-pronged strategy of targeting wild-type and mutant p53 in different subtypes of breast cancer can have clinical relevance. The development of p53-based therapies has rapidly progressed in recent years, and include unique small molecule chemical inhibitors, stapled peptides, PROTACs, as well as several genetic-based approaches using vectors and engineered antibodies. In this review, we highlight the therapeutic strategies that are in pre-clinical and clinical development to overcome p53 inactivation in both wild-type and mutant p53-bearing breast tumors, and discuss their efficacies and limitations in pre-clinical and clinical settings.

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Barriers to Immunotherapy in Ovarian Cancer: Metabolic, Genomic, and Immune Perturbations in the Tumour Microenvironment

Cited by 16 publications

References 344 publications

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Targeting tumor-associated macrophages for successful immunotherapy of ovarian carcinoma

Integrative Analysis From Multicenter Studies Identifies a WGCNA-Derived Cancer-Associated Fibroblast Signature for Ovarian Cancer

Role of p53 in breast cancer progression: An insight into p53 targeted therapy

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