The role of innate lymphoid cells (ILCs), including natural killer (NK) cells, is pivotal in inflammatory modulation and cancer. Natural killer cell activity and count have been demonstrated to be regulated by the expression of activating and inhibitory receptors together with and as a consequence of different stimuli. The great majority of NK cell populations have an anti-tumor activity due to their cytotoxicity, and for this reason have been used for cellular therapies in cancer patients. On the other hand, the recently classified helper ILCs are fundamentally involved in inflammation and they can be either helpful or harmful in cancer development and progression. Tissue niche seems to play an important role in modulating ILC function and conversion, as observed at the transcriptional level. In the past, these cell populations have been classified by the presence of specific cellular receptor markers; more recently, due to the advent of single-cell RNA sequencing (scRNA-seq), it has been possible to also explore them at the transcriptomic level. In this article we review studies on ILC (and NK cell) classification, function and their involvement in cancer. We also summarize the potential application of NK cells in cancer therapy and give an overview of the most recent studies involving ILCs and NKs at scRNA-seq, focusing on cancer. Finally, we provide a resource for those who wish to start single-cell transcriptomic analysis on the context of these innate lymphoid cell populations.
Breast cancer (BC) constitutes a major health problem worldwide, making it the most common malignancy in women. Current treatment options for BC depend primarily on histological type, molecular markers, clinical aggressiveness and stage of disease. Immunotherapy, such as αPD-1, have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC) delineating some therapeutic combinations as more effective than others. However, a clear overview of the main immune cell populations involved in these treatments has never been provided.Here, an assessment of the immune landscape in the tumor microenvironment (TME) of two TNBC mouse models has been performed using single-cell RNA sequencing technology. Specifically, immune cells were evaluated in untreated conditions and after treatments with chemotherapy or immunotherapy used as single agents or in combination. A decrease of Treg was found in treatments with in vivo efficacy as well as γδ T cells, which have a pro-tumoral activity in mice. Focusing on Cd8 T cells, across all the conditions, a general increase of exhausted-like Cd8 T cells was confirmed in pre-clinical treatments with low efficacy and an opposite trend was found for the proliferative Cd8 T cells. Regarding macrophages, M2-like cells were enriched in treatments with low efficacy while M1-like macrophages followed an opposite trend. For both models, similar proportions of B cells were detected with an increase of proliferative B cells in treatments involving cisplatin in combination with αPD-1. The fine-scale characterization of the immune TME in this work can lead to new insights on the diagnosis and treatment of TNBC.
Checkpoint inhibitors (CIs) such as anti-PD-1 and anti PD-L1 have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC), but only in a minority of patients and only for a limited period of time. Moreover, it is currently unclear what chemotherapeutic drug is the most appropriate to combine with CIs in TNBC patients. We have investigated at the single cell level the transcriptome and the trajectories of more than 50,000 innate and adaptive intratumoral immune cells in two syngeneic, immune competent, orthotopic murine models of local and metastatic TNBC. Mice injected with 4T1 cells had a predominant lymphoid infiltrate, mice injected with EMT6 cells had a predominant myeloid infiltrate. Mice were treated with CIs and several different types of chemotherapeutics, alone or in combinations. In both models, capecitabine (alone or with CIs) was the less effective drug. Platinum, doxorubicin and taxanes showed synergy with CIs and had superimposable activity. Intermittent, medium dosage cyclophosphamide (CTX) plus vinorelbine and CIs was the most active combinatorial therapy (Falvo et al, Cancer Research 2021). Vinorelbine activated antigen presenting cells and CTX generated new T cell clones including stem cell-like TCF1+ CD8+ T cells. Treatments with most in vivo efficacy were associated to a decrease of regulatory T cells and of gamma delta T cells, which were found to have a pro-tumoral activity in these murine models, likely due to IL-17 expression in the neoplastic microenvironment. An increase of several different clusters of exhausted-like CD8+ T cells was observed in pre-clinical treatments with low efficacy; an opposite trend was found for several clusters of proliferative CD8+ T cells in treatments with high in vivo efficacy. Regarding macrophages, M2-like cells were enriched after treatments with low efficacy, while an opposite behaviour was found in M1-like macrophages. Interestingly, we observed a significant increase of an M1-like cluster with high expression of the Ly6c1/Ly6c2 gene in mice successfully treated with vinorelbine, CTX and CIs. For both cell lines the percentage of plasma B cells increased after in vivo treatments with high efficacy. In particular, the most effective treatment significantly increased the frequency of germinal B cells, which were absent in untreated tumors. These data can lead to new insights on the diagnosis and treatment of TNBC and to possible clinical applications. Citation Format: Laura Carpen, Paolo Falvo, Stefania Orecchioni, Giulia Mitola, Roman Hillje, Saveria Mazzara, Patrizia Mancuso, Stefano Pileri, Alessandro Raveane, Francesco Bertolini. A single-cell RNA atlas of innate and adaptive intratumoral immunity in triple negative breast cancer during chemo- and immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1712.
Breast cancer (BC) constitutes a major health problem worldwide, making it the most common malignancy in women. Current treatment options for BC depend primarily on histological type, molecular markers, clinical aggressiveness and stage of disease. Immunotherapy, such as anti-PD-1, have shown combinatorial clinical activity with chemotherapy in triple negative breast cancer (TNBC) delineating some therapeutic combinations as more effective than others. However, a clear overview of the main immune cell populations involved in these treatments has never been provided.Here, an assessment of the immune landscape in the tumour microenvironment (TME) of two TNBC mouse models (4T1 and EMT6 cell lines) has been performed using single-cell RNA sequencing (scRNA-seq) technology. Specifically, immune cells were evaluated in untreated conditions and after being treated with chemotherapy or immunotherapy used as single agents or in combination. A decrease of regulatory T cells, compared to the untreated TME, was found in treatments with in vivo efficacy as well as γδ T cells, which have a pro-tumoral activity in mice. Focusing on Cd8 T cells, across all the conditions, a general increase of exhausted-like Cd8 T cells was confirmed in pre-clinical treatments with low efficacy; on the other hand, an opposite trend was found for the proliferative Cd8 T cells. Regarding macrophages, M2-like cells were found enriched in treatments with low efficacy while opposite behaviour was associated with M1-like macrophages. For both cell lines, similar proportions of B cells were detected with an increase of proliferative B cells in treatments that involved cisplatin in combination with anti-PD-1. The fine-scale characterization of the immune TME in this work can lead to new insights on the diagnosis and treatment of TNBC for a possible application at the clinical level.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
334 Leonard St
Brooklyn, NY 11211
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.