Two approaches to overcoming CAR antigen loss
One factor limiting chimeric antigen receptor (CAR) T-cell therapy efficacy against solid tumors is CAR antigen loss. Johnson et al. show that engineering CAR T cells to express the RNA RN7SL1 increases their antitumor efficacy in multiple models. RN7SL1 enhances CAR T-cell expansion and effector-memory differentiation, and also is transferred in extracellular vesicles to other immune cells that then promote activation of endogenous T cells that can reject solid tumors with CAR antigen loss. By testing various combinations of CAR constructs, Hirabayashi et al. find that T cells engineered to be dual targeting—with each CAR signaling through a different costimulatory endodomain, only one of which includes a CD3ζ-chain—provide the most effective antitumor effects and prevent antigen loss.
Local delivery of mRNA-encoded cytokines promotes antitumor immunity and tumor eradication across multiple preclinical tumor models
How to effectively deliver immunotherapy locally to tumors remains a challenge. Hotz et al. test the intratumoral delivery of a mixture of mRNAs encoding four cytokines/cytokine fusion proteins (IL12 single chain, IFNα4, GM-CSF, and IL15 sushi) in multiple tumor models. They find the treatment effectively activates antitumor immunity and induces immune memory; therapeutic effects are observed for primary, distant, and metastatic tumors. Combining the mRNA mixture with immune checkpoint blockade further enhances therapeutic benefit. The data suggest that this treatment strategy has the potential to improve current immunotherapy regimens, and it is now being tested in clinical trials.
The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer
Pancreatic adenocarcinoma (PDAC) is largely refractory to immunotherapy. Freed-Pastor et al. have developed organoid models of the subset of PDACs they predict to have high-affinity neoantigens and find that some of these organoids evade the immune system after transplantation into immune-competent mice. Immune-evasive organoids and human PDACs are infiltrated with dysfunctional neoantigen-specific CD8+ T cells and have high CD155 expression. Blockade of CD155/TIGIT signaling, together with anti–PD-1 blockade and CD40 agonism, limited immune evasion and CD40-agonist resistance in the mice, identifying a potential combination therapeutic strategy for PDAC.
The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation
Genetic screens for drivers of tumorigenesis are often conducted using systems that do not account for the complexity of the tumor microenvironment, including pressure exerted by the immune system. By performing transcriptome-wide CRISPR screens in mouse tumor models using animals with and without functional adaptive immunity, Martin et al. find an enrichment for loss of tumor suppressor genes as a requirement for tumor growth in the presence of an adaptive immune system. Loss of one tumor suppressor gene, GNA13, increases recruitment of tumor-associated macrophages by enhancing CCL2 secretion. These data highlight potential new functions for tumor suppressor genes that could be harnessed for immunotherapy.
An engineered IL-2 partial agonist promotes CD8+ T cell stemness
IL-2 is often used in the generation of T cells for adoptive cell therapy because it promotes T-cell expansion. However, it also induces terminal differentiation and expression of coinhibitory molecules, limiting therapeutic efficacy. Mo et al. identify an IL-2 partial agonist, H9T, that promotes CD8+ T–cell expansion but not terminal differentiation; rather, it drives transcriptional, epigenetic, and metabolic profiles that restrict T-cell exhaustion and maintain a stem cell–like state. T-cell receptor transgenic T cells and CAR T cells expanded with H9T show enhanced antitumor activity in mice compared with cells expanded in IL-2, highlighting the potential for engineering cytokines to increase adoptive cell therapy efficacy.
Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming
Tumor cells use various mechanisms to disseminate from the primary tumor to a metastatic site. Morrissey et al. show that tumor-derived exosomes drive polarization of macrophages in the premetastatic niche to an immune-suppressive phenotype, thereby promoting tumor metastasis. Macrophage interaction with tumor-derived exosomes leads to upregulation of PD-L1 and metabolic alterations, which act to further increase macrophage PD-L1 expression. The data highlight a feedback loop that potentiates immune suppression and identifies tumor-derived exosomes, macrophages, and metabolism-related factors as key players in the process.
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