Bone morphogenetic protein 7 promotes resistance to immunotherapy

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Immunotherapies, such as anti-PD1 therapy, have transformed cancer treatment.
• However, a significant number of patients exhibit resistance to these therapies.
• The underlying mechanisms of immunotherapy resistance remain largely unknown.

Purpose of the Study:

• To investigate the role of Bone Morphogenetic Protein 7 (BMP7) in mediating resistance to anti-PD1 therapy.
• To elucidate the molecular mechanisms by which BMP7 contributes to treatment resistance.
• To identify BMP7 as a potential therapeutic target for overcoming immunotherapy resistance.

Main Methods:

• Analysis of BMP7 expression in preclinical cancer models and patients with disease progression on immunotherapy.
• Investigating the effects of tumor-secreted BMP7 on immune cells (macrophages and CD4+ T cells) within the tumor microenvironment.
• Assessing the impact of BMP7 on MAPK14 expression and pro-inflammatory responses.
• Evaluating the efficacy of BMP7 knockdown or neutralization (using follistatin) in combination with anti-PD1 therapy.

Main Results:

• Overexpression of BMP7 was identified as a mechanism of resistance to anti-PD1 therapy.
• BMP7 secreted by tumor cells inhibits MAPK14 expression in macrophages and CD4+ T cells.
• This inhibition impairs crucial pro-inflammatory immune responses necessary for effective anti-tumor immunity.
• Knockdown or neutralization of BMP7, combined with anti-PD1 therapy, re-sensitized resistant tumors.

Conclusions:

• The BMP7 signaling pathway plays a critical role in mediating resistance to anti-PD1 immunotherapy.
• BMP7 acts within the tumor microenvironment to suppress anti-tumor immune responses.
• Targeting the BMP7 pathway presents a promising strategy to enhance the efficacy of cancer immunotherapy in resistant cases.