| Added by | Nathalie Bonnefoy |
|---|---|
| Group name | EquipeNB |
| Item Type | Journal Article |
| Title | Activin-A impairs CD8 T cell-mediated immunity and immune checkpoint therapy response in melanoma |
| Creator | Pinjusic et al. |
| Author | Katarina Pinjusic |
| Author | Olivier Andreas Dubey |
| Author | Olga Egorova |
| Author | Sina Nassiri |
| Author | Etienne Meylan |
| Author | Julien Faget |
| Author | Daniel Beat Constam |
| Abstract | Background Activin-A, a transforming growth factor ? family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear. Methods We analyzed the expression of the Activin-A encoding gene INHBA in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of BRAF-driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed INHBA expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models. Results We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of BRAF status by inhibiting CD8+ T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/INHBA expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models. Conclusions Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance. |
| Publication | Journal for Immunotherapy of Cancer |
| Volume | 10 |
| Issue | 5 |
| Pages | e004533 |
| Date | 2022-5-16 |
| Journal Abbr | J Immunother Cancer |
| DOI | 10.1136/jitc-2022-004533 |
| ISSN | 2051-1426 |
| URL | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125758/ |
| Accessed | 2022/07/25 - 11:46:18 |
| Library Catalog | PubMed Central |
| Extra | PMID: 35580932 PMCID: PMC9125758 |
| Tags | Immunotherapy, original |
| Date Added | 2022/07/25 - 09:46:18 |
| Date Modified | 2022/07/25 - 17:02:42 |
| Notes and Attachments | PubMed Central Link (Attachment) Texte intégral (Attachment) |
Institut de Recherche en Cancérologie de
