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Peptide Adjuvant to Invigorate Cytolytic Activity of NK Cells in an Obese Mouse Cancer Model
Seungmin Han1, Minjin Jung1, Angela S Kim1
1Division of Cardiothoracic Surgery, Department of Surgery, University of Arizona College of Medicine-Tucson, Tucson, AZ 85724, USA.
Abstract:
Cancer patients who are overweight compared to those with normal body weight have obesity-associated alterations of natural killer (NK) cells, characterized by poor cytotoxicity, slow proliferation, and inadequate anti-cancer activity. Concomitantly, prohibitin overexpressed by cancer cells elevates glucose metabolism, rendering the tumor microenvironment (TME) more tumor-favorable, and leading to malfunction of immune cells present in the TME. These changes cause vicious cycles of tumor growth. Adoptive immunotherapy has emerged as a promising option for cancer patients; however, obesity-related alterations in the TME allow the tumor to bypass immune surveillance and to down-regulate the activity of adoptively transferred NK cells. We hypothesized that inhibiting the prohibitin signaling pathway in an obese model would reduce glucose metabolism of cancer cells, thereby changing the TME to a pro-immune microenvironment and restoring the cytolytic activity of NK cells. Priming tumor cells with an inhibitory the prohibitin-binding peptide (PBP) enhances cytokine secretion and augments the cytolytic activity of adoptively transferred NK cells. NK cells harvested from the PBP-primed tumors exhibit multiple markers associated with the effector function of active NK cells. Our findings suggest that PBP has the potential as an adjuvant to enhance the cytolytic activity of adoptively transferred NK cells in cancer patients with obesity.
Insights
Obesity impairs natural killer (NK) cell anti-cancer activity. Inhibiting prohibitin with a peptide restores NK cell function, offering a potential therapy for obese cancer patients.
Area of Science:
- Immunology
- Oncology
- Metabolic Disorders
Background:
- Obesity is linked to impaired natural killer (NK) cell function and reduced anti-cancer activity.
- Cancer cells overexpress prohibitin, increasing glucose metabolism and creating a tumor-promoting microenvironment (TME) that hinders immune cell function.
- Adoptive immunotherapy efficacy is compromised in obese patients due to TME-induced suppression of transferred NK cells.
Purpose of the Study:
- To investigate if inhibiting the prohibitin signaling pathway can reverse obesity-associated TME alterations and restore NK cell anti-cancer activity.
- To evaluate the potential of a prohibitin-binding peptide (PBP) as an adjuvant therapy to enhance adoptive NK cell immunotherapy in obese cancer patients.
Main Methods:
- Utilized an obese cancer model to assess the effects of prohibitin inhibition on the TME and NK cell function.
- Administered a prohibitin-binding peptide (PBP) to prime tumor cells.
- Analyzed changes in glucose metabolism, TME composition, and NK cell cytotoxicity, proliferation, and effector function markers.
Main Results:
- Inhibiting prohibitin signaling reduced cancer cell glucose metabolism, shifting the TME towards a pro-immune state.
- Priming tumor cells with PBP enhanced NK cell cytokine secretion and cytolytic activity.
- NK cells from PBP-treated tumors displayed markers of enhanced effector function.
Conclusions:
- Targeting prohibitin with PBP can reprogram the TME in obese cancer models, overcoming immune suppression.
- PBP shows promise as an adjuvant therapy to augment the efficacy of adoptive NK cell immunotherapy in obese cancer patients.
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