Granulocyte colony-stimulating factor impairs CD8+ T cell functionality by interfering with central activation elements

Bunse, Carola E.; Tischer, Sabine; Lahrberg, Julia; Oelke, Mathias; Figueiredo, Constança; Blasczyk, Rainer

doi:10.1111/cei.12794

Cited by 22 publications

(21 citation statements)

References 46 publications

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“…The changes in tumor growth were associated with changes in T cell-associated cytokine production. IL-10 was substantially decreased in G-CSFR −/− mice, which is in agreement with previous reports (26,32), suggesting G-CSF supports regulatory T cells. Furthermore, a drastic increase in IFNγ and IL-17A was observed.…”

Section: Discussionsupporting

confidence: 93%

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

et al. 2020

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Cytokines are known to shape the tumor microenvironment and although progress has been made in understanding their role in carcinogenesis, much remains to learn regarding their role in tumor growth and progression. We have identified granulocyte colony-stimulating factor (G-CSF) as one such cytokine, showing that G-CSF is linked with metastasis in human gastrointestinal tumors and neutralizing G-CSF in a mouse model of colitis-associated cancer is protective. Here, we set out to identify the role of G-CSF and its receptor, G-CSFR, in CD4 + and CD8 + T cell responses in the tumor microenvironment. MC38 colon cancer cells were injected into WT, G-CSFR −/− mice, or Rag2 −/− mice. Flow cytometry, Real Time PCR and Multiplex cytokine array analysis were used for in vitro T cell phenotype analysis. Adoptive transfer of WT or G-CSFR −/− CD4 + of CD8 + T cells were performed. Mouse tumor size, cytokine expression, T cell phenotype, and cytotoxic activity were analyzed. We established that in G-CSFR −/− mice, tumor growth of MC38 colon cancer cells is significantly decreased. T cell phenotype and cytokine production were also altered, as both in vitro and in vivo approaches revealed that the G-CSF/G-CSFR stimulate IL-10-producing, FoxP3-expressing CD4 + and CD8 + T cells, whereas G-CSFR −/− T cells exhibit increased IFNγ and IL-17A production, leading to increased cytotoxic activity in the tumor microenvironment. Furthermore, peritumoral injection of recombinant IFNγ or IL-17A inhibited colon and pancreas tumor growth compared to controls. Taken together, our data reveal an unknown mechanism by which G-CSF, through its receptor G-CSFR, promotes an inhibitory Treg phenotype that limits tumor immune responses and furthermore suggest that targeting this cytokine/receptor axis could represent a novel therapeutic approach for gastrointestinal, and likely other tumors with high expression of these factors.

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Section: Discussionsupporting

confidence: 93%

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

et al. 2020

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“…To get first insights on the effects of cytokines on CB T cells compared to PB T cells, CD8+ T cells were stimulated with human T‐activator CD3/CD28 Dynabeads (Life Technologies) according to the manufacturer's instructions in aAPC medium (RPMI 1640 supplemented with 5% heat‐inactivated human AB serum [c.c.pro], 1% sodium pyruvate [Sigma Aldrich], 0.4% modified Eagle's medium vitamins, 1% nonessential amino acids [both Life Technologies], and 50 U/mL IL‐2), supplemented with IL‐7 and IL‐15 alone and in combination with IL‐12 and/or IL‐21 (all 10 ng/mL, PeproTech) for 7 days.…”

Section: Methodsmentioning

confidence: 99%

“…For antigen-specific stimulation, aAPCs were generated by coupling HLA-A*02:01 molecules (DimerX, BD) loaded with HLA-A*02:01-restricted MART1 peptide (Melan-A 26-35 A27L , ELAGIGILTV, ProImmune) and anti-CD28 MoAbs (BD) onto M-450 epoxy beads (Life Technologies) as previously described. 25,26 Isolated CD81 CB and PB T cells were cultured in aAPC medium supplemented with the different cytokine combinations as described in Polyclonal T-cell activation and proliferation assay. On Day 7, T cells were stimulated for a further period as specified above using peptide-loaded aAPCs with additional 50 U/mL IL-2.…”

Section: Mart1-reactive Cd81 T-cell Stimulation Using Hla-ig-based Aapcsmentioning

confidence: 99%

Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

et al. 2017

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BACKGROUND Transplantation of hematopoietic stem cells (HSCs) from peripheral blood (PB) or cord blood (CB) is well established. HSCs from CB are associated with a lower risk of graft‐versus‐host disease (GVHD), but antigen‐independent expanded CB‐ and PB‐derived T cells can induce GVHD in allo‐HSC recipients. CB‐derived cells might be more suitable for adoptive immunotherapy as they have unique T‐cell characteristics. Here, we describe functional differences between CB and PB T cells stimulated with different cytokine combinations involved in central T‐cell activation. STUDY DESIGN AND METHODS Isolated CD8+ T cells from CB and PB were stimulated antigen independently with anti‐CD3/CD28 stimulator beads or in an antigen‐dependent manner with artificial antigen‐presenting cells loaded with the HLA‐A*02:01‐restricted peptide of tumor‐associated melanoma antigen recognized by T cells 1 (MART1). CB and PB T cells cultured in the presence of interleukin (IL)‐7, IL‐15, IL‐12, and IL‐21 were characterized for T‐cell phenotype and specificity, that is, by CD107a, interferon‐γ, tumor necrosis factor‐α, and IL‐2 expression. RESULTS After antigen‐independent stimulation, activated CD8+ CB T cells exhibited stronger proliferation and function than those from PB. After antigenic stimulation, MART1‐reactive CB T cells were naïve (CD45RA+CCR7+), cytotoxic, and highly variable in expressing homing marker CD62L. Addition of IL‐21 resulted in increased T‐cell proliferation, whereas supplementation with IL‐12 decreased IL‐21–induced expansion, but increased the functionality and cytotoxicity of CB and PB T cells. CONCLUSION MART1‐reactive CB T cells with a more naïve phenotype and improved properties for homing can be generated. The results contribute to better understanding the effects on GVHD and graft versus tumor.

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“…conceivably impede the impact of lymphodepletion as a break from immune tolerance [26]. More 460 generally, however, the broader impact of immune system augmentation or suppression during therapy 461 remains unexamined.…”

mentioning

confidence: 99%

The Goldilocks Window of Personalized Chemotherapy: An Immune Perspective

D¹,

Robertson-Tessi²,

Luddy³

et al. 2018

Preprint

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The immune system is increasingly being recognized for its untapped potential in being recruited to attack tumors in cancer therapy. The main challenge, however, is that most tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. In order to investigate the ability to use chemotherapy to break immune tolerance, we created a mathematical modeling framework for tumor-immune dynamics. Our results suggest that optimal chemotherapy scheduling must balance two opposing objectives: maximal tumor reduction and preserving patient immune function. Successful treatment requires therapy to operate in a "Goldilocks Window" where patient immune health is not overly compromised. By keeping therapy "just right", we show that the synergistic effects of immune activation and chemotherapy can maximize tumor reduction and control.

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Granulocyte colony-stimulating factor impairs CD8+ T cell functionality by interfering with central activation elements

Cited by 22 publications

References 46 publications

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

G-CSF and G-CSFR Modulate CD4 and CD8 T Cell Responses to Promote Colon Tumor Growth and Are Potential Therapeutic Targets

Cord blood–derived T cells allow the generation of a more naïve tumor‐reactive cytotoxic T‐cell phenotype

The Goldilocks Window of Personalized Chemotherapy: An Immune Perspective

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