Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer

Kersten, Kelly; Hu, Kenneth H.; Combes, Alexis J.; Samad, Bushra; Harwin, Tory; Ray, Arja; Av, Rao; Cai, En; Marchuk, Kyle; Artichoker, Jordan; Courau, Tristan; Shi, Quanming; Belk, Julia A.; Satpathy, Ansuman T.; Krummel, Matthew F.

doi:10.1016/j.ccell.2022.05.004

Cited by 176 publications

(131 citation statements)

References 88 publications

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“…Similar observations have been made in kidney cancer, and T cell attracting myeloid immune cell hubs have recently been described in colorectal tumors, indicating that spatially organized immune cell clusters are required for intratumoral immune cell crosstalk, and ultimately, the maintenance of functional anti-tumor responses (Jansen et al, 2019;Pelka et al, 2021). Others have recently described a spatial co-dependency of intratumoral macrophages and exhausted CD8 + T cells in hypoxic tumor regions (Kersten et al, 2021).…”

Section: Discussionsupporting

confidence: 70%

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Kilian

Sheinin

Tan

et al. 2022

Preprint

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Cancer immunotherapy critically depends on fitness of cytotoxic and helper T cell responses. Dysfunctional cytotoxic T cell states in the tumor microenvironment (TME) are a major cause of resistance to immunotherapy. Intratumoral myeloid cells, particularly blood-borne myeloids (bbm), are key drivers of T cell dysfunction in the TME. We show here that major histocompatibility complex (MHC) class II (MHCII)-restricted antigen presentation on bbm is essential to control the growth of brain tumors. Loss of MHCII on bbm drives dysfunctional intratumoral tumor-reactive CD8+ T cell states through increased chromatin accessibility and expression of Tox, a critical regulator of T cell exhaustion. Mechanistically, MHCII-dependent activation of CD4+ T cells restricts myeloid-derived osteopontin that triggers a chronic activation of nuclear factor of activated T cells (Nfat)2 in tumor-reactive CD8+ T cells. In summary, we provide evidence that MHCII-restricted antigen presentation on bbm is a key mechanism to directly maintain functional cytotoxic T cell states in brain tumors.

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Section: Discussionsupporting

confidence: 70%

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Kilian

Sheinin

Tan

et al. 2022

Preprint

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“…In our dataset, LAG3 +/CD103+ CD4 Tfh cells and LAG3+ /CD103+ exhausted CD8 T cells expressed many RNA signatures and protein markers in common, supporting the proposition that the TME can influence lymphocytes to acquire neophenotypes outside common lineage-associated phenotypes (Figure 5). Given their shared inflammatory gene expression, including CCL chemokines and CSF1, and co-localisation with macrophages, we hypothesise that both exhausted populations promote inflammation outside of lymphoid structures, which has recently been proposed in mouse models (Kersten et al, 2021). As both increased macrophage infiltration and increased exhaustion of T cells are strongly linked with patient prognosis (Cassetta et al, 2019; Foroutan et al, 2021), further studies on the downstream effect of exhaustion on adjacent immune cells within the TME is vital.…”

Section: Discussionmentioning

confidence: 88%

Integration of single-cell RNA and protein data identifies novel clinically-relevant lymphocyte phenotypes in breast cancers

Al-Eryani

Bartoniček

Chan

et al. 2022

Preprint

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Immune cells are critical determinants of solid tumour aetiology, but the diverse phenotypes of intra-tumoural immune cells remain incompletely characterised. We applied integrated single cell RNA sequencing (scRNA-Seq) and highly multiplexed protein epitope analysis to a cohort of breast cancer samples to resolve cell states within the tumour microenvironment. We reveal novel protein markers for resting and activated tumour infiltrating lymphocytes, and show that high expression of CD103 primarily marks exhausted CD8 rather than tissue resident CD8 T-cells in human breast cancers. We identify two distinct states of activated CD4+ T follicular helper (Tfh) cells. A population resembling conventional Tfh (cTfh) cells were localised primarily to lymphoid aggregates by spatial transcriptomics. In contrast, cancer associated Tfh (caTfh) cells expressing markers of tissue residency and exhaustion co-localized with cancer foci and signalled to macrophages. Importantly, increased caTfh : cTfh ratio associated with improved disease outcome and response to checkpoint immunotherapy.

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“…Interestingly, these TAMs efficiently activated naive T cells, but had rather inhibitory effects on previously activated CD8 + T cells, unless supplemented with IL-2 or TLR signals. Likewise, CD8 + T cells help shape the differentiation of TAMs, as Colony stimulating factor 1 (CSF1) release by exhausted CD8 + T cells was shown to favor antigen-presentation transcriptional programs in tumor-infiltrating monocytes [ 55 ].…”

Section: Local Reactivation Of T Cells By Macrophage Antigen Presenta...mentioning

confidence: 99%

“…These observations reveal two important aspects of CD8 + T cell activation in tumors. First, macrophages can cross-present antigens to CD8 + T cells, but in the absence of additional signals, this causes T cells to undergo exhaustion [ 55 ], a frequently observed state in tumors [ 56 ]. Secondly, these results suggest that TAM and CD8 + T cell co-activation should be investigated in the context of tumor regression, in which the abundant presence of pro-inflammatory signals, mimicked by TLR signals [ 53 ], could favor effector T cell re-activation.…”

Section: Local Reactivation Of T Cells By Macrophage Antigen Presenta...mentioning

confidence: 99%

Dynamic CD8+ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy

Vermare

Guérin

Peranzoni

et al. 2022

Cancers

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The essential roles endorsed by macrophages and monocytes are well established in response to infections, where they contribute to launching the differentiation of specific T-lymphocytes for long-term protection. This knowledge is the result of dynamic studies that can inspire the cancer field, particularly now that cancer immunotherapies elicit some tumor regression. Indeed, immune responses to cancer have mainly been studied after tumors have escaped immune attacks. In particular, the suppressive functions of macrophages were revealed in this context, introducing an obvious bias across the literature. In this review, we will focus on the ways inwhich monocytes and macrophages cooperate with T-lymphocytes, leading to successful immune responses. We will bring together the preclinical studies that have revealed the existence of such positive cooperation in the cancer field, and we will place particular emphasis on proposing the underlying mechanisms. Finally, we will give some perspectives to decipher the functional roles of such T-cell and myeloid cell interactions in the frame of human cancer immunotherapy.

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Spatiotemporal co-dependency between macrophages and exhausted CD8+ T cells in cancer

Cited by 176 publications

References 88 publications

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

MHC class II-restricted antigen presentation is required to prevent dysfunction of cytotoxic T cells by blood-borne myeloids in brain tumors

Integration of single-cell RNA and protein data identifies novel clinically-relevant lymphocyte phenotypes in breast cancers

Dynamic CD8+ T Cell Cooperation with Macrophages and Monocytes for Successful Cancer Immunotherapy

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