NLRP3 agonist enhances radiation-induced immune priming and promotes abscopal responses in anti-PD1 resistant model.

Radiotherapy (XRT), a well-known activator of the inflammasome and immune priming, is in part capable of reversing resistance to anti-PD1 treatment. The NLRP3 inflammasome is a pattern recognition receptor which is activated by both exogenous and endogenous stimuli, leading to a downstream inflammatory response. Although NLRP3 is typically recognized for its role in exacerbating XRT-induced tissue damage, the NLRP3 inflammasome can also yield an effective antitumor response when used in proper dosing and sequencing with XRT. However, whether NLRP3 agonist boosts radiation-induced immune priming and promote abscopal responses in anti-PD1 resistant model is still unknown. Therefore, in this study, we paired intratumoral injection of an NLRP3 agonist with XRT to stimulate the immune system in both wild type (344SQ-P) and anti-PD1 resistant (344SQ-R) murine-implanted lung adenocarcinoma models. We found that the combination of XRT + NLPR3 agonist enhanced the control of implanted lung adenocarcinoma primary as well as secondary tumors in a radiological dose-dependent manner, in which 12Gyx3 fractions of stereotactic XRT was better than 5Gyx3, while 1Gyx2 did not improve the NLRP3 effect. Survival and tumor growth data also showed significant abscopal response with the triple therapy (12Gyx3 + NLRP3 agonist + α-PD1) in both 344SQ-P and 344SQ-R aggressively growing models. Multiple pro-inflammatory cytokines (IL-1b, IL-4, IL-12, IL-17, IFN-γ and GM-CSF) were elevated in the serum of mice treated with XRT + NLRP3 or triple therapy. The Nanostring results showed that NLRP3 agonist is capable of increasing antigen presentation, innate function, and T-cell priming. This study can be of particular importance to treat patients with immunologically-cold solid tumors whom are also refractory to prior checkpoint treatments.

Lipid metabolism in tumor immunology and immunotherapy.

Lipids are a diverse class of biomolecules that have been implicated in cancer pathophysiology and in an array of immune responses, making them potential targets for improving immune responsiveness. Lipid and lipid oxidation also can affect tumor progression and response to treatment. Although their importance in cellular functions and their potential as cancer biomarkers have been explored, lipids have yet to be extensively investigated as a possible form of cancer therapy. This review explores the role of lipids in cancer pathophysiology and describes how further understanding of these macromolecules could prompt novel treatments for cancer.

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.

Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.

Corrigendum: Lipid metabolism in tumor immunology and immunotherapy.

[This corrects the article DOI: 10.3389/fonc.2023.1187279.].