Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer

Marcheteau, Elie; Farge, Thomas; Pérès, Michaël; Labrousse, Guillaume; Tenet, Julie; Delmas, Stéphanie; Chusseau, Maud; Duprez-Paumier, Raphaëlle; Franchet, Camille; Imbert, Caroline; Noujarède, Justine; Colacios, Céline; Piégay, Hervé; Cabon, Florence; Ségui, Bruno

doi:10.3390/cancers13164059

Cited by 9 publications

(5 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of the many immunosuppressive genes we observed, Thbs1 is a secreted glycoprotein implicated in a wide range of processes [52]. Blocking Thbs1 with a genetic approach in triple-negative breast cancer (TNBC) was shown to increase CD8 T cells infiltration/proliferation and improve response to αPD-L1 immunotherapy in mice [53]. To our knowledge, there is no validated pharmacological inhibitor of Thbs1 available.…”

Section: Discussionmentioning

confidence: 99%

Therapy-induced senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Beauséjour

Maggiorani

Lê

et al. 2023

Preprint

View full text Add to dashboard Cite

Immune checkpoint inhibitors (ICI) invigorate immune cell functions and are effective against many cancer types. However, the potential of ICI may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of αPD-L1-based cancer immunotherapies is compromised by the accumulation of senescent cells in mice previously exposed to sublethal irradiation or injected with doxorubicin. Similarly, we observed that the efficacy of the combination of a αCTLA-4 antibody with radiotherapy is diminished in previously irradiated mice. In both models, resistance to immunotherapy was associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells by the injection of the senolytic drug ABT263, weeks before treatments, restored immune homeostasis within the tumor micro-environment (TME) and increased mice survival in both models. Using single-cell transcriptomic analysis, we observed that the injection of ABT263 reverses the exacerbated immunosuppressive profile of myeloid cells in the TME of previously irradiated mice. These myeloid cells, when purified from established tumors, were responsible for impaired CD8 T cell proliferation in vitro. Our study shows that cancer therapies, by inducing senescence, favor the formation of an immunosuppressive TME, which can alter the efficacy of ICI. The use of senolytic drugs before ICI may constitute an interesting pharmacological approach to improve the effectiveness of cancer immunotherapies.

show abstract

Section: Discussionmentioning

confidence: 99%

Therapy-induced senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Beauséjour

Maggiorani

Lê

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Of the many immunosuppressive genes we observed, Thbs1 is a secreted glycoprotein implicated in a wide range of processes 50 . Blocking Thbs1 with a genetic approach in triple-negative breast cancer (TNBC) was shown to increase CD8 T cells infiltration/proliferation and improve response to αPD-L1 immunotherapy in mice 51 . To our knowledge, there is no validated pharmacological inhibitor of Thbs1 available.…”

Section: Discussionmentioning

confidence: 99%

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Maggiorani,

Le,

Lisi

et al. 2024

Nat Commun

View full text Add to dashboard Cite

The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

show abstract

“…However, the role of THBS1 in recruiting CD8 + T cells had been reported rarely. But THBS1 knockdown indirectly increased CD8 + TILs by increasing tumor vascularization in triple-negative breast cancer [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

BRAF D594A mutation defines a unique biological and immuno-modulatory subgroup associated with functional CD8+ T cell infiltration in colorectal cancer

Li,

Zhao,

et al. 2023

J Transl Med

View full text Add to dashboard Cite

Background BRAF non-V600 mutation occupies a relatively small but critical subset in colorectal cancer (CRC). However, little is known about the biological functions and impacts of BRAF class III mutation in CRC. Here, we aim to explore how D594A mutation impacts on biological behaviors and immune related signatures in murine CRC cells. Methods BRAF V600E (class I), G469V (class II) and D594A (class III) mutant cell lines were established based on MC38 cells. The biological behaviors of cells were evaluated in respect of cell growth, cell proliferation, cell apoptosis, cell migration and invasion by the methods of colony-forming assay, CCK-8 assay, Annexin V/PI staining and transwell assay. The concentrations of soluble cytokines were detected by ELISA. The membrane expression of immuno-modulatory molecules and the pattern of tumor infiltrating lymphocyte were evaluated by flow cytometry. The molecular mechanism was explored by RNA sequencing. Immunohistochemistry (IHC) staining was used for the detection of CD8α in tumor tissues. qRT-PCR and western blot were performed to assess the mRNA and protein expression. Anti-PD-L1 treatment and cytokines neutralization experiments were conducted in in vivo models. Results D594A mutant cells displayed lower grade malignancy characteristics than V600E (class I) and G469V (class II) mutant cells. Meanwhile, D594A mutation led to evident immuno-modulatory features including upregulation of MHC Class I and PD-L1. In vivo experiments displayed that the frequency of infiltrated CD8+ T cells was significantly high within D594A mutant tumors, which may provide potential response to anti-PD-L1 therapy. RNA sequencing analysis showed that D594A mutation led to enhanced expression of ATF3 and THBS1, which thus facilitated CXCL9 and CXCL10 production upon IFN-γ treatment. In addition, CXCL9 or CXCL10 neutralization reduced the infiltration of CD8+ T cells into THBS1-overexpressing tumors. Conclusions D594A mutant CRC exhibited lower aggressiveness and immune-activated phenotype. ATF3-THBS1-CXCL9/CXCL10 axis mediated functional CD8+ T cells infiltration into the microenvironment of D594A mutant CRC. Our present study is helpful to define this mutation in CRC and provide important insights in designing effective immunotherapeutic strategies in clinic.

show abstract

Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer

Cited by 9 publications

References 41 publications

Therapy-induced senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Therapy-induced senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

Senescence drives immunotherapy resistance by inducing an immunosuppressive tumor microenvironment

BRAF D594A mutation defines a unique biological and immuno-modulatory subgroup associated with functional CD8+ T cell infiltration in colorectal cancer

Contact Info

Product

Resources

About