This month's featured editor is Dr. Pedro J. Romero, Editor-in-Chief.
“PD-1-cis IL-2R agonism yields better effectors from stem-like CD8+ T cells” by Laura Codarri Deak et al
Interleukin (IL)-2 is an essential cytokine and growth factor for T cell expansion and differentiation. While IL-2 has been utilized as a cancer immunotherapy, the presence of the alpha chain of the IL-2 receptor (IL-2R-α, CD25) on non-tumor tissues leads to severe toxicity and high expression of CD25 on Tregs can result in immunosuppression. Laura Codarri Deak and colleagues engineered an IL-2 receptor agonist that circumvents CD25 binding by docking on PD-1. The engineered agonist preferentially targeted and expanded CD8+ stem-like cells over CD4+ T cells and/or exhausted CD8+ T cells, allowing for increased differentiation into a CD8+ effector memory population capable of inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) and granzyme B secretion. In transplanted mouse pancreatic adenocarcinoma models, the engineered agonist eradicated tumors and induced effector tumor infiltrating lymphocytes (TILs). Interestingly, monotherapy with the engineered agonist was more effective than high dose IL-2 monotherapy or high dose IL-2 in combination with anti-PD-1 therapy, and activity of the engineered agonist was not enhanced by the addition of anti-PD-1. Responses were also seen in mouse models of cancers typically unresponsive to anti-PD-1 therapy, including a sarcoma and pancreatic neuroendocrine tumor. Single-cell gene expression and T cell receptor (TCR) analyses confirmed that the engineered agonist induced a highly efficient, polyfunctional, tumor-specific effector TIL population.
Why this matters: This study demonstrates pre-clinical efficacy of an engineered fusion protein with targeted IL-2 agonist activity that is more potent and, in principle, safer than the previous parental cytokine. The single-agent activity and efficacy in models of anti-PD-1-unresponsive tumors are encouraging signals for further development of this approach.
“Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions” by Lian Narunsky-Haziza et al
Polymorphic microbiomes are now recognized as a hallmark of cancer, with bacterial influences on tumor phenotypes and anticancer immunity being an active area of research. The non-bacterial constituents of the microbiota, however, have received relatively scant attention. Lian Narunsky-Haziza and colleagues comprehensively characterized fungal communities across 35 tumor types in four independent patient cohorts, revealing cancer-specific ecologies of interaction between bacteria, fungi, and the immune system. While the richness of fungal diversity was lower than that seen for bacteria, distinct mycobiome signatures could be described for individual tumor types. In a pan-cancer analysis, three distinct “mycotypes” were defined by co-occurrence of specific fungi, bacteria, and immune cells. Specific fungi were significantly linked to clinically relevant disease features, for example, the presence of fungi in the genome cladosporium significantly associated with younger age of onset and HER2-negativity in breast cancer and anti-PD-1 resistance in melanoma. Detection of fungal DNA in serum differentiated samples from patients with cancer versus healthy controls with reasonable sensitivity and specificity in both pan-tumor and tissue-specific analyses. Importantly, serum fungal DNA signatures not only identified advanced disease but also distinguished samples from patients with stage I cancer versus healthy controls.
Why this matters: Fungi are ubiquitous yet understudied. These findings add further insight into the complex, multi-kingdom interactions within the tumor microenvironment and set the stage for future mechanistic studies into the interplay between fungi, cancer, and the immune system.
“Tumor immune contexture is a determinant of anti-CD19 CAR T cell efficacy in large B cell lymphoma” by Nathalie Scholler et al
Nature Medicine (2022)
Chimeric antigen receptor (CAR) T cell therapy is curative for some patients with large B cell lymphomas (LBCL), however, almost half of all treated patients relapse within the first year and determinants of resistance beyond target loss or silencing remain poorly understood. To clarify the role of the tumor immune contexture in response to CAR T cell therapy, Nathalie Scholler and colleagues performed comprehensive gene expression analyses and multiplex spatial tissue analysis on pre- and on-treatment biopsies from patients enrolled in the pivotal ZUMA-1 trial that lead to regulatory approval of the CD19-directed product axicabtagene ciloleucel. As expected, the post-treatment tumor microenvironment from patients with responsive disease was characterized by elevated expression of genes related to T cell cytotoxicity, T cell growth factors, interferon signaling, and myeloid-related chemokines. CAR T cell expansion inversely correlated with infiltration of exhausted T cells and the highest numbers of circulating CAR T cells were observed in patients that had the highest densities of helper T cells in the tumor microenvironment. Pre-treatment T cell infiltration, helper T cell densities, and Immunoscore signatures all were associated with significantly improved overall survival. Notably, patients who experienced high-grade neurologic adverse events had dramatically reduced pre-treatment intratumoral regulatory T cell (Treg) densities. Distinct from solid tumors, infiltrating Tregs were positively associated with features favoring response and patients with high densities of both Tregs and effector T cells achieved complete remissions without neurologic toxicity.
Why this matters: No validated biomarkers have been described to predict durable response or toxicity with CAR T cell therapy. These findings reveal new insight into the contribution of endogenous lymphocyte populations on efficacy of adoptive cell therapy and identify pre-treatment signatures to assist in patient selection.
“Breast cancer cell-derived microRNA-155 suppresses tumor progression via enhancing immune cell recruitment and antitumor function” by Junfeng Wang et al
J Clin Invest (2022)
MicroRNA-155 has been shown to promote oncogenesis in solid tumors and hematologic malignancies. However, upregulation of microRNA-155 has also been associated with improved overall survival in breast cancer, colon cancer, and melanoma. To resolve this apparent contradiction, Junfeng Wang and colleagues investigated the role of microRNA-155 in antitumor immune response versus tumorigenesis in human datasets and murine breast cancer models. In human breast tumor datasets from The Cancer Genome Atlas, high expression of microRNA-155 was associated with signatures of antitumor immune cells (eg, CD8+ T cells, M1 macrophages) and prolonged survival. In orthotopic mammary tumor models, enforced overexpression of microRNA-155 delayed tumor growth, with increased infiltrating dendritic cells, helper and cytotoxic T cells, and tumoricidal natural killer cells. Underscoring the role of mircroRNA-155 in generating a specific anti-tumor immune response, mice with resected microRNA-155-overexpressing tumors rejected subsequent rechallenge. Conditioned media from microRNA-155 overexpressing cells contained exosomes and was enriched for CCL5 and CXCL9/10 chemoattractants and markedly reduced SOCS1 with a concomitant increase in phosphorylated STAT-1 to STAT-3 ratios was seen in the cells. Serum microRNA-155 levels correlated with tumor-infiltrating CD8+ T cells in mice and were significantly associated with tumor expression of IL-2, CD8A, and IFNG, with qPCR in human datasets.
Why this matters: These findings establish microRNA-155 as a positive mediator of anti-tumor immunity in breast cancer. Because serum levels associated with immune infiltration and expression of checkpoints in breast tumors, microRNA-155 might potentially be developed into a noninvasive biomarker for patient selection for immunotherapy.
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