Faculty Opinions recommendation of Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103(+) dendritic cells in late-stage ovarian cancer.

Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.

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Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

Nature Communications ◽

10.1038/s41467-021-25684-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jianhuang Lin ◽

Heng Liu ◽

Takeshi Fukumoto ◽

Joseph Zundell ◽

Qingqing Yan ◽

...

Keyword(s):

Ovarian Cancer ◽

Stress Response ◽

Er Stress ◽

Cancer Cells ◽

Immune Checkpoint ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

Ovarian Cancer Cells ◽

Dependent Manner ◽

Er Stress Response

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

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Novel therapeutics: response and resistance in ovarian cancer

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2019-000456 ◽

2019 ◽

Vol 29 (Suppl 2) ◽

pp. s16-s21 ◽

Cited By ~ 2

Author(s):

Dmitriy Zamarin

Keyword(s):

Ovarian Cancer ◽

Cancer Research ◽

Immune Checkpoint ◽

Parp Inhibitors ◽

Immune Checkpoint Blockade ◽

Cell Cycle Checkpoint ◽

Checkpoint Blockade ◽

The Novel ◽

Novel Therapeutics ◽

Dna Damaging Agents

Here we review the latest pre-clinical and clinical developments for treatment of ovarian cancer, presented at the American Association of Cancer Research/Rivkin Center Ovarian Cancer Research Symposium held at the University of Washington in September 2018. Abstracts and presentations pertaining to the 'Novel Therapeutics' session were reviewed and are summarized here. The session featured a keynote presentation from Dr Ursula Matulonis, who summarized the current state of the art of treatment of ovarian cancer, including recent clinical trials incorporating the use of novel agents, including poly-ADP-ribose polymerase (PARP) inhibitors, other DNA-damaging agents, vascular endothelial growth factor receptor inhibitors, mirvetuximab soravtansine, and immune checkpoint blockade. Dr Jung-Min Lee then summarized the rationale and the results of early studies for targeting cell cycle checkpoint kinases for anti-cancer therapy. Eight submissions were selected for oral presentations, and 36 abstracts were presented as posters. The topics covered a range of clinical and pre-clinical strategies and biomarkers, including immunotherapy, mechanisms of chemotherapy, and PARP inhibitor resistance, DNA-damaging agents, and other novel therapeutic strategies. Key studies have highlighted that resistance to chemotherapy and PARP inhibitors remain a major challenge in therapy of ovarian cancer. Cancer stem cells represent an important mechanism of chemoresistance and strategies to target these cells may be a pathway to prevention of ovarian cancer relapse. Advancement of novel therapeutics targeting DNA damage, cell metabolism, and endoplasmic reticulum present some of the novel strategies in the pipeline. Emerging compelling pre-clinical data with novel antibody-drug conjugates targeting various surface receptors in ovarian cancer alone and in combination with immune checkpoint blockade generate a strong enthusiasm for rapid translation of these strategies to clinic.

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