Single cell RNA-sequence reveals the effect of neoadjuvant chemotherapy on immune cells in human esophageal squamous cell carcinoma.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE197677 | GEO | 2023/03/31
REPOSITORIES: GEO
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Project description:Properly applying current immunotherapies or developing novel therapeutic strategies relies on a comprehensive understanding of the immune elements of the tumor microenvironment (TME). In this study, we aim to map at single-cell resolution the immune landscape of esophagus squamous cell carcinoma (ESCC), a common, aggressive, but understudied cancer of the gastrointestinal tract. We obtained a detailed immune cell atlas of the ESCC-associated transcriptome from a total of 80,787 tumor-infiltrating immune cells. Significant intertumoral heterogeneity was found among individual ESSC tumors. Exhausted T cells, exhausted NK cells, regulatory T cells, alternatively activated macrophages, and tolerogenic dendritic cells were discovered as the dominant portions of the immune cells in the TME. Dysfunctional T cells were the major proliferative cell compartment among tumor-infiltrating immune cells. In addition, strong potential interactions of immune cells in tumors may contribute to the immunosuppressive status and the progress of tumor development; a six-gene signature, comprising IFNGR1, IFNGR2, IDO1, IL10, CD163, and CD274, were associated with ESCC survival. Our results provided a comprehensive characterization of tumor-infiltrating immune cells in ESCC, indicating that immunosuppression of various kinds was synchronously responsible for the failure of immunosurveillance in ESCC. Specifically targeting the immunosuppressive pathways could reverse the immune-suppressive status and reactivate anti-tumor immune responses in ESCC.
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Project description:Immunotherapy of immunologically cold solid tumors may require multiple agents to (a) engage immune effector cells, (b) expand effector populations and activities, and (c) enable immune response in the tumor microenvironment (TME). To target these distinct phenomena, we strategically chose five clinical-stage immuno-oncology agents, namely, (a) a tumor antigen-targeting adenovirus-based vaccine (Ad-CEA) and an IL-15 superagonist (N-803) to activate tumor specific T cells, (b) OX40 and GITR agonists to expand and enhance the activated effector populations, and (c) an IDO inhibitor (IDOi) to enable effector cell activity in the TME. Flow cytometry, TCR sequencing, and RNAseq analyses showed that in the CEA-transgenic murine colon carcinoma (MC38-CEA) tumor model, Ad-CEA + N-803 combination therapy resulted in immune-mediated anti-tumor effects and promoted the expression of costimulatory molecules on immune subsets, OX40 and GITR, and the inhibitory molecule IDO. Treatment with Ad-CEA + N-803 + OX40 + GITR + IDOi, termed the pentatherapy regimen, resulted in the greatest inhibition of tumor growth and protection from tumor rechallenge without toxicity. Monotherapy with any of the agents had little to no anti-tumor activity, while combining two, three, or four agents had minimal anti-tumor effects. Immune analyses demonstrated that the pentatherapy combination induced CD4+ and CD8+ T cell activity in the periphery and tumor and anti-tumor activity associated with decreased Treg immunosuppression in the TME. The pentatherapy combination also inhibited tumor growth and metastatic formation in 4T1 and LL2-CEA murine tumor models. Significance: This study provides the rationale for the combination of multi-modal immunotherapy agents to engage, enhance, and enable adaptive anti-tumor immunity.
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Project description:N6-methyladenosine (m6A) in messenger RNA (mRNA) regulates immune cells in homeostasis and in response to infection and inflammation. The function of YTHDF2 in the tumor microenvironment (TME) in these contexts has not been explored. We discovered that loss of Ythdf2 in regulatory T (Treg) cells can reduce tumor growth in mice while maintaining peripheral homeostasis. In the tumor microenvironment, Ythdf2-deficient Treg cells have impaired function and poor survival. The elevated tumor necrosis factor (TNF) signaling in the TME grants the location-specific function of YTHDF2, which participates in the feedback regulation of NF-kB signaling by accelerating the degradation of m6A-modified, NF-kB negative regulators, Nlrc3, Nfkbie, and Traf3. TME-specific regulation of Treg by YTHDF2 points to YTHDF2 as a target for anti-cancer immunotherapy, where intratumoral Treg cells can be targeted to enhance antitumor immune response, while avoiding Treg cells in the periphery to minimize undesired inflammations.
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