Baseline Frequency of Inflammatory Cxcl9-Expressing Tumor-Associated Macrophages Predicts Response to Avelumab Treatment

Qü, Yan; Wen, Ji; Thomas, Graham D.; Yang, Wenjing; Prior, Weiwei; He, Wenqian; Sundar, Purnima; Wang, Xiao; Potluri, Shobha; Salek-Ardakani, Shahram

doi:10.1016/j.celrep.2020.107873

Cited by 49 publications

(49 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As immune cells have already been shown to have predictive value underlined by the introduction of immune checkpoint inhibitors and the evaluation of PD-L1 expression in some cancers (although not yet lung cancer [37]), it is likely that more comprehensive characterizations of the immune tumor microenvironment will provide even deeper insights in patient stratification and drug development. Recently, expression of the proinflammatory cytokines CXCL9 and CXCL10 by tumor-associated macrophages, for instance, has been shown to be essential for tumor response to anti-PD-L1 therapy [38, 39]. Interestingly, we observed high expression of these cytokines in pro-inflammatory monocyte-derived macrophages indicating that the microenvironmental CEP 2 pattern, which was also marked by exhausted CD8+ T cells, could be a predictor of response to anti-PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Bischoff

Trinks

Obermayer

et al. 2020

Preprint

View full text Add to dashboard Cite

Recent developments in immuno-oncology demonstrate that not only cancer cells, but also features of the tumor microenvironment guide precision medicine. Still, the relationship between tumor and microenvironment remains poorly understood. To overcome this limitation and identify clinically relevant microenvironmental and cancer features, we applied single-cell RNA sequencing to lung adenocarcinomas. While the highly heterogeneous carcinoma cell transcriptomes reflected histological grade and activity of relevant oncogenic pathways, our analysis revealed two distinct microenvironmental patterns. We identified a prognostically unfavorable group of tumors with a microenvironment composed of cancer-associated myofibroblasts, exhausted CD8+ T cells, proinflammatory monocyte-derived macrophages and plasmacytoid dendritic cells (CEP2 pattern) and a prognostically favorable group characterized by myeloid dendritic cells, anti-inflammatory monocyte-derived macrophages, normal-like myofibroblasts, NK cells and conventional T cells (MAN2C pattern). Our results show that single-cell gene expression profiling allows to identify patient subgroups based on the tumor microenvironment beyond cancer cell-centric profiling.

show abstract

Section: Discussionmentioning

confidence: 99%

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Bischoff

Trinks

Obermayer

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…10 Cxcr3-deficient mice possess substantially increased tumor volumes compared with wild type (WT) controls following the PD1 blockade. Our group has also recently shown that blocking CXCR3 and CXCL9 impair anti-PD-L1 efficacy in CT26 colorectal carcinoma, 25 while CXCR3 inhibition impairs the efficacy of dual anti-PD1 and anti-cytotoxic T lymphocytes antigen-4 (CTLA-4) regimen in multiple tumor models. 12 Disruption of the CXCL9-CXCR3 axis is associated with reduced infiltration of peripheral CD8 T cells into the TME 10 27 (figure 1A), while PD1 blockade increases tumor mRNA expression and circulating protein levels of CXCL9 and CXCL10.…”

Section: Heterogeneity Of Macrophages and Their Precursors Implies Anmentioning

confidence: 98%

“…Mac_9 cells shared an inflammatory gene signature with M3 TAMs, with both coexpressing multiple genes, including Cxcl9, Cxcl10, MHCII, Cd40 and Stat1. 25 A recent transcriptomic profiling study of TAMs from lung cancer patients also identified variable expression of inflammatorymacrophage-associated genes, most notably Cxcl9, Cxcl10 and Stat1 ascribed to an 'M1 hot ' phenotype. 30 Genes associated with this M1 hot state, including Cxcl9, correlated with increased survival and a higher density of intratumorous CD8 T cells indicating that human myeloid populations bearing a highly similar transcriptional state to murine Cxcl9 expressing-TAMs correlate with survival and accumulation of CD8 T cells in human cancer.…”

Section: Heterogeneity Of Macrophages and Their Precursors Implies Anmentioning

confidence: 99%

“…Our group recently employed a bilateral tumor model to understand immune correlates of response to avelumab (anti-PD-L1) treatment. 25 By implanting CT26 colorectal carcinoma subcutaneously into both flanks, we used single-cell RNA-Seq to profile the TME before treatment with Avelumab while tracking treatment response in the contralateral tumor. Of the 26 immune cell populations identified in the TME, only a single subset correlated positively with the response to avelumab.…”

Section: Heterogeneity Of Macrophages and Their Precursors Implies Anmentioning

confidence: 99%

“…This M3 population was distinct from cDC subsets, monocytes and mature macrophages. 25 However, it appeared to be monocyte-derived based on single-cell trajectory analysis. Notably, M3 TAMs expressed uniquely high levels of Cxcl9, alongside MHCII, Cd40, Cd274 (PD-L1), Stat1, Nos2 and Cd38 as well as intermediate levels of Itgax (CD11c).…”

Section: Heterogeneity Of Macrophages and Their Precursors Implies Anmentioning

confidence: 99%

See 2 more Smart Citations

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

Marcovecchio

Thomas

Salek-Ardakani

2021

J Immunother Cancer

Self Cite

View full text Add to dashboard Cite

Tumor-associated macrophages (TAMs) are among the main contributors to immune suppression in the tumor microenvironment, however, TAM depletion strategies have yielded little clinical benefit. Here, we discuss the concept that TAMs are also key regulators of anti-PD(L)-1-mediated CD8 T cell-dependent immunity. Emerging data suggest that expression of the chemokine CXCL9 by TAMs regulates the recruitment and positioning of CXCR3-expressing stem-like CD8 T (Tstem) cells that underlie clinical responses to anti-PD(L)-1 treatment. We evaluate clinical and mechanistic studies that establish relationships between CXCL9-expressing TAMs, Tstem and antitumor immunity. Therapies that enhance anti-PD(L)-1 response rates must consider TAM CXCL9 expression. In this perspective, we discuss opportunities to enhance the frequency and function of CXCL9 expressing TAMs and draw on comparative analyzes from infectious disease models to highlight potential functions of these cells beyond Tstem recruitment.

show abstract

Pharmacological Polarization of Tumor‐Associated Macrophages Toward a CXCL9 Antitumor Phenotype

Enbergs,

Halabi,

Goubet

et al. 2024

Advanced Science

View full text Add to dashboard Cite

Tumor‐associated macrophages (TAM) are a diverse population of myeloid cells that are often abundant and immunosuppressive in human cancers. CXCL9Hi TAM has recently been described to have an antitumor phenotype and is linked to immune checkpoint response. Despite the emerging understanding of the unique antitumor TAM phenotype, there is a lack of TAM‐specific therapeutics to exploit this new biological understanding. Here, the discovery and characterization of multiple small‐molecule enhancers of chemokine ligand 9 (CXCL9) and their targeted delivery in a TAM‐avid systemic nanoformulation is reported. With this strategy, it is efficient encapsulation and release of multiple drug loads that can efficiently induce CXCL9 expression in macrophages, both in vitro and in vivo in a mouse tumor model. These observations provide a window into the molecular features that define TAM‐specific states, an insight a novel therapeutic anticancer approach is used to discover.

show abstract

Baseline Frequency of Inflammatory Cxcl9-Expressing Tumor-Associated Macrophages Predicts Response to Avelumab Treatment

Cited by 49 publications

References 31 publications

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

Single-cell RNA sequencing reveals distinct tumor microenvironmental patterns in lung adenocarcinoma

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

Pharmacological Polarization of Tumor‐Associated Macrophages Toward a CXCL9 Antitumor Phenotype

Contact Info

Product

Resources

About