Dataset Information

Profiling of tumor-infiltrating natural killer (NK) cells and macrophages in untreated C57BL/6 mice and mice treated with combination immunotherapies

ABSTRACT: Treatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here we demonstrate a single-dose combination treatment (termed AIP) employing a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-PD-1, which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. NK cells and macrophages activated by AIP treatment underwent transcriptional reprogramming, rapidly killed cancer cells, governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes, and induced normalization of the tumor vasculature, facilitating further immune infiltration. In order to parse out the contribution of each components in the 1X AIP treatment, we examined NK cells and macrophages from B16F10-bearing mice treated with AIP, AI, IP and AP or left untreated.

ORGANISM(S): Mus musculus

PROVIDER: GSE184599 | GEO | 2023/06/22

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background: T cell-based immunotherapies including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells can induce durable responses in cancer patients. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of Natural Killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their Major Histocompatibility Complex class I (MHC I) expression due to acquired resistance mechanisms. However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy. Method: In this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compound on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated utilizing compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types. Results: The screening approach led to the identification of a Cbl-b inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with TIGIT blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells. Conclusion: These findings underscore the relevance of Cbl-b inhibition in overcoming NK cells dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for cancer patients.

Dataset Information

Profiling of tumor-infiltrating natural killer (NK) cells and macrophages in untreated C57BL/6 mice and mice treated with combination immunotherapies

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets