Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors Journal Article
| Authors: | Rudqvist, N. P.; Charpentier, M.; Lhuillier, C.; Wennerberg, E.; Spada, S.; Sheridan, C.; Zhou, X. K.; Zhang, T.; Formenti, S. C.; Sims, J. S.; Alonso, A.; Demaria, S. |
| Article Title: | Immunotherapy targeting different immune compartments in combination with radiation therapy induces regression of resistant tumors |
| Abstract: | Radiation therapy (RT) increases tumor response to CTLA-4 inhibition (CTLA4i) in mice and in some patients, yet deep responses are rare. To identify rational combinations of immunotherapy to improve responses we use models of triple negative breast cancer highly resistant to immunotherapy in female mice. We find that CTLA4i promotes the expansion of CD4+ T helper cells, whereas RT enhances T cell clonality and enriches for CD8+ T cells with an exhausted phenotype. Combination therapy decreases regulatory CD4+ T cells and increases effector memory, early activation and precursor exhausted CD8+ T cells. A combined gene signature comprising these three CD8+ T cell clusters is associated with survival in patients. Here we show that targeting additional immune checkpoints expressed by intratumoral T cells, including PD1, is not effective, whereas CD40 agonist therapy recruits resistant tumors into responding to the combination of RT and CTLA4i, indicating the need to target different immune compartments. © 2023, Springer Nature Limited. |
| Keywords: | survival; multimodality cancer therapy; combined modality therapy; cd8+ t lymphocyte; cd8-positive t-lymphocytes; mouse; animal; animals; mice; gene expression; immunotherapy; tumor; triple negative breast cancer; cd40 antigen; cell component; cancer; humans; human; female; triple negative breast neoplasms; cd40 antigens |
| Journal Title: | Nature Communications |
| Volume: | 14 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-08-24 |
| Start Page: | 5146 |
| Language: | English |
| DOI: | 10.1038/s41467-023-40844-3 |
| PUBMED: | 37620372 |
| PROVIDER: | scopus |
| PMCID: | PMC10449830 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Scopus |
