CX3CR1–CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment

Yamauchi, Takayoshi; Hoki, Toshifumi; Oba, Takaaki; Saito, Hiroyoshi; Attwood, Kristopher; Sabel, Michael S.; Chang, Alfred E.; Odunsi, Kunle; Ito, Fumito

doi:10.1172/jci.insight.133920

Cited by 55 publications

(57 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MC38 tumor-bearing Cd2-cre/Cx3cr1+/DTR mice were treated with AdpgkMut/TLR3/CD40 vaccination, and received phosphate buffer saline (PBS) or DT injections every day starting 1 day before vaccination ( Figure 6B). We found that depletion of CX3CR1+CD8+ T cells did not alter antitumor efficacy of neoantigen vaccination ( Figure 6C), in line with our recent study using a mouse model of adoptive T-cell therapy (15), suggesting that CX3CR1+ CD8+ T cells might not be functionally relevant to the established tumors while their frequency in PB correlates with response to the treatment.…”

Section: In Vivo Antitumor Efficacy Of Antigen-specific Cx3cr1+cd8+ Tsupporting

confidence: 90%

“…Vaccine-primed CX3CR1+CD8+ T cells expressed low levels of CD62L and CXCR3, trafficking receptors necessary for entry across lymphoid organ HEV and the tumor microvasculature (16,17), respectively, that may have contributed to increase its frequency in PB. Furthermore, unlike other T-cell proliferation, activation or co-stimulatory/inhibitory molecules transiently expressed after activation, CX3CR1 is stably expressed on CD8+ T cells through unidirectional differentiation from CX3CR1-CD8+ T cells during the effector phase (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, adoptive transfer of CX3CR1+CD8+ T cells did not affect tumor growth nor survival while the CX3CR1-subset displayed potent antitumor efficacy (15).…”

Section: In Vivo Antitumor Efficacy Of Antigen-specific Cx3cr1+cd8+ Tmentioning

confidence: 95%

“…For tetramer staining, PE-labeled MHC class I (H-2Db) specific for mouse AdpgkMut 299-307 (ASMTNMELM) (18) was kindly provided by the NIH Tetramer Core Facility. Detection of intracellular cytokines, GZMA, IFN-γ and TNF-α was performed as described before (15,61).…”

Section: Flow Cytometry and Intracellular Granzyme Tnf-α And Ifn-γ Amentioning

confidence: 99%

“…The chemokine receptor, CX3CR1, was recently identified as a marker of effector T-cell differentiation (13,14). Unlike other proliferation, co-stimulatory and co-inhibitory molecules such as Ki67, ICOS, PD-1 and CTLA-4 that are only transiently upregulated on T cells after activation, CX3CR1 is stably expressed on virus-and tumor-specific CD8+ T cells upon differentiation via unidirectional differentiation from the CX3CR1-subset during the effector phase (13)(14)(15). Furthermore, our study and others have shown that CD8+ T cells expressing high levels of CX3CR1 exhibit decreased expression of L-selectin (CD62L) and CXCR3 (13)(14)(15), trafficking receptors necessary for entry across lymphoid organ high endothelial venules (HEV) and the tumor microvasculature (16,17), respectively, and become more prevalent in PB at the end of the effector phase (14,15), suggesting a potential advantage as a circulating Tcell biomarker.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice

Yamauchi

Hoki

Oba

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Running title: CX3CR1 as a circulating biomarker for vaccine therapy 33 34 Word counts (excluding abstract and references): 2,476 35 36 Abstract 38Background The use of tumor mutation-derived neoantigen represents a promising approach for 39 cancer vaccines. Preclinical and early-phase human clinical studies have shown the successful 40 induction of tumor neoepitope-directed responses; however, overall clinical efficacy of 41 neoantigen vaccines has been limited. One major limitation of this strategy is the lack of a 42 reliable blood-based surrogate marker for clinical response. Here, we investigated a role of 43 CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation in predicting response 44 to neoantigen vaccination in a preclinical model. 45Methods Mice bearing MC38 colon adenocarcinoma cells that harbor a single-epitope mutation 46 within the Adpgk protein were treated with mutant Adpgk peptide (AdpgkMut) in combination 47 with toll-like receptor 3 (TLR3) agonist poly(I:C) and/or anti-CD40 antibody (Ab). Antitumor 48 efficacy of neoantigen vaccination and the frequency of peripheral blood AdpgkMut-specific 49 CX3CR1+CD8+ T cells were assessed. Mechanisms underlying the generation of CX3CR1+CD8+ 50 T cells were examined using knockout and bone marrow chimeric mice. 51 ResultsWe found that CD40 stimulation significantly enhanced antitumor efficacy of 52 neoantigen and TLR3 agonist vaccination, which was associated with an increased frequency of 53 circulating AdpgkMut-specific effector CX3CR1+CD8+ T cells. Generation of neoantigen-specific 54 CX3CR1+CD8+ T cells by AdpgkMut/CD40/TLR3 stimulation was dependent on CD40 and Batf3 55 in bone marrow-derived cells. Further mechanistic studies using mixed bone marrow chimeras 56identified key roles for CD40 and CD80/86, but not CD70 signaling in Batf3-dependent 57 conventional type 1 dendritic cells (cDC1s) for generation of neoantigen-specific cytotoxic 58 CX3CR1+CD8+ T cells and therapeutic efficacy of neoantigen vaccine. 59Conclusions Taken together, our results underscore critical roles of cDC1s and an implication of 60 dual CD40/TLR3 stimulation in neoantigen-based therapeutic vaccines, and demonstrate the 61 potential utility of CX3CR1 as a circulating predictive T-cell biomarker in vaccine clinical trials. 62 63

show abstract

Section: In Vivo Antitumor Efficacy Of Antigen-specific Cx3cr1+cd8+ Tsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

“…Furthermore, adoptive transfer of CX3CR1+CD8+ T cells did not affect tumor growth nor survival while the CX3CR1-subset displayed potent antitumor efficacy (15).…”

Section: In Vivo Antitumor Efficacy Of Antigen-specific Cx3cr1+cd8+ Tmentioning

confidence: 95%

Section: Flow Cytometry and Intracellular Granzyme Tnf-α And Ifn-γ Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice

Yamauchi

Hoki

Oba

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Immunological link between periodontitis and type 2 diabetes deciphered by single‐cell RNA analysis

Lee,

Joo,

Song

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundType 2 diabetes mellitus (DM) is a complex metabolic disorder that causes various complications, including periodontitis (PD). Although a bidirectional relationship has been reported between DM and PD, their immunological relationship remains poorly understood. Therefore, this study aimed to compare the immune response in patients with PD alone and in those with both PD and DM (PDDM) to expand our knowledge of the complicated connection between PD and DM.MethodsPeripheral blood mononuclear cells were collected from 11 healthy controls, 10 patients with PD without DM, and six patients with PDDM, followed by analysis using single‐cell RNA sequencing. The differences among groups were then compared based on intracellular and intercellular perspectives.ResultsCompared to the healthy state, classical monocytes exhibited the highest degree of transcriptional change, with elevated levels of pro‐inflammatory cytokines in both PD and PDDM. DM diminished the effector function of CD8+ T and natural killer (NK) cells as well as completely modified the differentiation direction of these cells. Interestingly, a prominent pathway, RESISTIN, which is known to increase insulin resistance and susceptibility to diabetes, was found to be activated under both PD and PDDM conditions. In particular, CAP1+ classical monocytes from patients with PD and PDDM showed elevated nuclear factor kappa B‐inducing kinase activity.ConclusionsOverall, this study elucidates how the presence of DM contributes to the deterioration of T/NK cell immunity and the immunological basis connecting PD to DM.

show abstract

Biomarkers and experimental models for cancer immunology investigation

Xu,

Jia,

Liu

et al. 2023

MedComm

View full text Add to dashboard Cite

The rapid advancement of tumor immunotherapies poses challenges for the tools used in cancer immunology research, highlighting the need for highly effective biomarkers and reproducible experimental models. Current immunotherapy biomarkers encompass surface protein markers such as PD‐L1, genetic features such as microsatellite instability, tumor‐infiltrating lymphocytes, and biomarkers in liquid biopsy such as circulating tumor DNAs. Experimental models, ranging from 3D in vitro cultures (spheroids, submerged models, air–liquid interface models, organ‐on‐a‐chips) to advanced 3D bioprinting techniques, have emerged as valuable platforms for cancer immunology investigations and immunotherapy biomarker research. By preserving native immune components or coculturing with exogenous immune cells, these models replicate the tumor microenvironment in vitro. Animal models like syngeneic models, genetically engineered models, and patient‐derived xenografts provide opportunities to study in vivo tumor‐immune interactions. Humanized animal models further enable the simulation of the human‐specific tumor microenvironment. Here, we provide a comprehensive overview of the advantages, limitations, and prospects of different biomarkers and experimental models, specifically focusing on the role of biomarkers in predicting immunotherapy outcomes and the ability of experimental models to replicate the tumor microenvironment. By integrating cutting‐edge biomarkers and experimental models, this review serves as a valuable resource for accessing the forefront of cancer immunology investigation.

show abstract

CX3CR1–CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment

Cited by 55 publications

References 54 publications

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice

Immunological link between periodontitis and type 2 diabetes deciphered by single‐cell RNA analysis

Biomarkers and experimental models for cancer immunology investigation

Contact Info

Product

Resources

About

CX3CR1–CD8+ T cells are critical in antitumor efficacy but functionally suppressed in the tumor microenvironment

Cited by 55 publications

References 54 publications

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1+ CD8+ T cells in mice

Immunological link between periodontitis and type 2 diabetes deciphered by single‐cell RNA analysis

Biomarkers and experimental models for cancer immunology investigation

Contact Info

Product

Resources

About

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice

CD40 and CD80/86 signaling in cDC1s mediate effective neoantigen vaccination and generation of antigen-specific CX3CR1⁺ CD8⁺ T cells in mice