期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：22
DOI：10.1073/pnas.2200568119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Immunotherapy provides long-term remissions in numerous types of cancer but is ineffective in most tumors with poor immune cell infiltrates or lacking T cell epitopes or MHC I molecules. Agents that activate the STING protein showed promise in several MHC I
+ and MHC-deficient tumor models in mice, where they induced powerful antitumor CD8
+ T cell and natural killer (NK) cell responses, respectively. They were less effective in numerous other tumor models and yielded mixed results in the clinic in human patients. This report demonstrates strong synergy between a STING agonist and an IL-2 superkine in effectively curing difficult-to-treat MHC-deficient and MHC-positive tumor models in mice by mobilizing T cells and NK cells. This combination therapy shows considerable promise for clinical application.
Cyclic dinucleotides (CDN) and Toll-like receptor (TLR) ligands mobilize antitumor responses by natural killer (NK) cells and T cells, potentially serving as complementary therapies to immune checkpoint therapy. In the clinic thus far, however, CDN therapy targeting stimulator of interferon genes (STING) protein has yielded mixed results, perhaps because it initiates responses potently but does not provide signals to sustain activation and proliferation of activated cytotoxic lymphocytes. To improve efficacy, we combined CDN with a half life-extended interleukin-2 (IL-2) superkine, H9-MSA (mouse serum albumin). CDN/H9-MSA therapy induced dramatic long-term remissions of the most difficult to treat major histocompatibility complex class I (MHC I)–deficient and MHC I
+ tumor transplant models. H9-MSA combined with CpG oligonucleotide also induced potent responses. Mechanistically, tumor elimination required CD8 T cells and not NK cells in the case of MHC I
+ tumors and NK cells but not CD8 T cells in the case of MHC-deficient tumors. Furthermore, combination therapy resulted in more prolonged and more intense NK cell activation, cytotoxicity, and expression of cytotoxic effector molecules in comparison with monotherapy. Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA with checkpoint therapy yielded long-term remissions in the majority of the animals, mediated by T cells and NK cells. This combination therapy has the potential to activate responses in tumors resistant to current therapies and prevent MHC I loss accompanying acquired resistance of tumors to checkpoint therapy.
