Cytotoxic T cells swarm by homotypic chemokine signalling

Niño, Jorge Luis Galeano; Pageon, Sophie V.; Tay, Szun S.; Colakoglu, Feyza; Kempe, Daryan; Hywood, Jack D.; Mazalo, Jessica K; Cremasco, James; Govendir, Matt A.; Dagley, Laura F.; Hsu, Ku‐Lung; Rizzetto, Simone; Zieba, Jerzy; Rice, Gregory; Prior, Victoria; O’Neill, Geraldine M.; Williams, Richard J.; Nisbet, David R.; Kramer, Belinda; Webb, Andrew I.; Luciani, Fabio; Read, Mark; Biro, Maté

doi:10.7554/elife.56554

Cited by 68 publications

(67 citation statements)

References 63 publications

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“…The current results confirm recently published observations [24] that show a CCR5-mediated swarming of T-cells in-vitro , as well as in-vivo studies that report the accumulation of T-cells on targets [25, 26], Figure 3 shows that these effects occur even for cell populations consisting of a few individuals and that a single contact can trigger the beginning of the positive feedback. Below we go beyond the CTL accumulation to address the relationship between the accumulation of CTLs and their capacity to kill the B16 spheroids.…”

Section: Resultssupporting

confidence: 92%

“…Several mechanisms may account for the collaborative CTL accumulation and killing. Chemokines that are both sensed and produced by T cells have the ability to drive their swarming behaviour [24]. Cooperative killing, in which multiple sublethal cytotoxic hits synergize to induce target cell killing, has been previously described in the context of viral infection [30] and tumor development [31].…”

Section: Discussionmentioning

confidence: 99%

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A Multiscale Immuno-Oncology on-Chip System (MIOCS) establishes that collective T cell behaviors govern tumor regression

Ronteix

Jain

Angely

et al. 2021

Preprint

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T cell-based tumor immunotherapies such as CAR T cells or immune checkpoint inhibitors harness the cytotoxic potential of T cells to promote tumor regression. However, patient response to immunotherapy remains heterogeneous, highlighting the need to better understand the rules governing a successful T cell attack. Here, we develop a microfluidic-based method to track the outcome of T cell activity on many individual cancer spheroids simultaneously, with a high spatiotemporal resolution. By combining these parallel measurements of T cell behaviors and tumor fate with probabilistic modeling, we establish that the first recruited T cells initiate a positive feedback loop leading to an accelerated effector accumulation on the spheroid. We also provide evidence that cooperation between T cells on the spheroid during the killing phase facilitates tumor destruction. We propose that tumor destruction does not simply reflect the sum of individual T cell activities but relies instead on collective behaviors promoting both T cell accumulation and function. The possibility to track many replicates of immune-tumor interactions with such a level of detail should help delineate the mechanisms and efficacy of various immunotherapeutic strategies.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

A Multiscale Immuno-Oncology on-Chip System (MIOCS) establishes that collective T cell behaviors govern tumor regression

Ronteix

Jain

Angely

et al. 2021

Preprint

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“…This data showed a major suppressive role of CCL6 on T cell proliferation in vitro , which has not been previously reported and might explain the enhanced immunomodulatory properties of BM-PHC over MSC. However, the specific blocking of CCR1 (reported as the putative receptor of CCL6) ( 37 ), using BX471 small molecule, totally suppressed T cell proliferation ( Supplemental Figure 6A ), which probably reflected the involvement of other CC chemokines, such as CCL3, or CCL5 (which are synthetized by T cells and also signalize through CCR1 ( 43 , 44 ), in cell survival and proliferation.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Hematopoietic Cell Population Emerging From Mouse Bone Marrow With Proliferative Potential In Vitro and Immunomodulatory Capacity

Marinescu¹,

Preda²,

Neculachi³

et al. 2021

Front. Immunol.

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There is continuing interest in therapeutic applications of bone marrow-derived mesenchymal stromal cells (MSC). Unlike human counterparts, mouse MSC are difficult to propagate in vitro due to their contamination with adherent hematopoietic cells that overgrow the cultures. Here we investigated the properties of these contaminating cells, referred to as bone marrow-derived proliferating hematopoietic cells (BM-PHC). The results showed that both BM-PHC and MSC had strong immunomodulatory properties on T cells in vitro, with PGE2 and NO involved in this mechanism. However, BM-PHC were stronger immunomodulators than MSC, with CCL-6 identified as putative molecule responsible for superior effects. In vivo studies showed that, in contrast to BM-PHC, MSC endorsed a more rapid xenograft tumor rejection, thus indicating a particular context in which only MSC therapy would produce positive outcomes. In conclusion, bone marrow contains two cell populations with immunomodulatory properties, which are valuable sources for therapeutic studies in specific disease-relevant contexts.

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“…The decreased number of NK cells indicates that the immune system is less capable of monitoring, killing, and clearing tumor cells [27]. Hence, the detection of the ACL in tumor patients is of great signi cance for understanding the changes of patients' condition and prognosis [28].…”

Section: Discussionmentioning

confidence: 99%

Absolute Counts of Peripheral Lymphocyte Subsets as Potential Immune Impairment Markers in Patients With Breast Cancer

Liu¹,

Xia²,

Li³

et al. 2021

Preprint

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Purpose This study was to evaluate clinic value of absolute counts of lymphocyte subsets (ACL) as potential blood biomarkers in progression and prognosis in breast cancer (BC) patients.Methods A total of 237 BC patients and 55 age-matched female normal healthy donors (normal cantrals, NCs) were enrolled in this study. The absolute counts (AC) and percentages of CD3+, CD3+CD4+, CD3+CD8+, B and NK cells were determined by flow cytometry. The clinicopathological parameters influencing disease progression were determined by binary logistic regression. The progression-free survival (PFS) was evaluated by Kaplan-Meier. Univariable and multivariable analyses were performed using log-rank test and proportional hazard regression models, respectively.Results Compared with NCs, the ACL in BC patients decreased significantly, while the percentages of lymphocytes showed no change. Of them, AC of CD3+CD4+ cells was closely related to clinical stages. The ACL, especially CD3+CD4+ cells, were affected by different treatments. Analysis of logistic regression showed that the cut-off value of CD3+CD4+ cells ≥ 451 cells/μL was the favorable prognostic factor. Multivariate analysis of prognostic factors of PFS showed CD3+CD4+ and CD3+CD8+ cells were independent factors for predicting PFS.Conclusions The AC of CD3+, CD3+CD4+, CD3+CD8+, B, and NK cells in BC patients were impaired obviously and can be as potential susceptive indications to evaluate the patient's immune states. The higher level of AC of CD3+CD4+ and CD3+CD8+ cells contributed to longer PFS and favorable outcome, and could help to adopt appropriate treatment strategies in clinic.

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Cytotoxic T cells swarm by homotypic chemokine signalling

Cited by 68 publications

References 63 publications

A Multiscale Immuno-Oncology on-Chip System (MIOCS) establishes that collective T cell behaviors govern tumor regression

A Multiscale Immuno-Oncology on-Chip System (MIOCS) establishes that collective T cell behaviors govern tumor regression

Identification of a Hematopoietic Cell Population Emerging From Mouse Bone Marrow With Proliferative Potential In Vitro and Immunomodulatory Capacity

Absolute Counts of Peripheral Lymphocyte Subsets as Potential Immune Impairment Markers in Patients With Breast Cancer

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