Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance

Area of Science:

• Oncology
• Immunology
• Cellular Biology

Background:

• Caloric restriction mimetics (CRMs) mimic nutrient deprivation by reducing lysine acetylation and inducing autophagy.
• Autophagy plays a role in regulating cellular processes and immune responses.
• Regulatory T cells (Tregs) can suppress anti-cancer immunity.

Purpose of the Study:

• To investigate the effect of CRMs on autophagy-competent and deficient KRAS-induced lung cancers.
• To determine if CRMs can enhance the efficacy of chemotherapy.
• To explore the role of Tregs in CRM-mediated anti-cancer effects.

Main Methods:

• Treatment of mice with mutant KRAS-induced lung cancers with hydroxycitrate, a CRM.
• Assessment of Treg populations in tumors.
• Evaluation of tumor growth inhibition by chemotherapy in conjunction with CRMs or short-term fasting.
• Analysis of tumor-infiltrating lymphocytes.

Main Results:

• Hydroxycitrate depleted Tregs from autophagy-competent, but not autophagy-deficient, KRAS-induced lung cancers, improving immunosurveillance and reducing tumor mass.
• Short-term fasting and unrelated CRMs (hydroxycitrate, spermidine) enhanced chemotherapy's tumor growth inhibition in autophagy-competent tumors.
• These effects were dependent on T lymphocytes and accompanied by Treg depletion from the tumor bed.

Conclusions:

• CRMs can enhance anti-cancer therapy by modulating the tumor microenvironment through autophagy.
• Targeting autophagy with CRMs may be a viable strategy to improve cancer immunotherapy and chemotherapy outcomes.
• The depletion of Tregs is a key mechanism by which CRMs exert their anti-cancer effects.