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Expansion of circulating stem-like CD8⁺ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

ABSTRACT: Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8⁺ T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8⁺ T cells expand in the blood; these cells express the chemokine receptor CXCR3, which is required for migration into tumors. In tumor tissue, effector-like but not terminally differentiated exhausted CD8⁺ T cells increase. Consistent with the surge in tumor-specific CD8⁺ T cells in blood that are migration and proliferation competent, we observe a CD8-dependent and CXCR3-dependent enhancement of the abscopal effect against distant/non-irradiated tumors and find that CD8⁺ T cells isolated from blood after RT/anti-PD1/IL-2c triple treatment can be a rich source of tumor-specific T cells for adoptive transfers.

SUBMITTER: Onyshchenko K

PROVIDER: S-EPMC10097749 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Expansion of circulating stem-like CD8<sup>+</sup> T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

Onyshchenko Kateryna K Luo Ren R Guffart Elena E Gaedicke Simone S Grosu Anca-Ligia AL Firat Elke E Niedermann Gabriele G

Nature communications 20230412 1

Combination of radiation therapy (RT) with immune checkpoint blockade can enhance systemic anti-tumor T cell responses. Here, using two mouse tumor models, we demonstrate that adding long-acting CD122-directed IL-2 complexes (IL-2c) to RT/anti-PD1 further increases tumor-specific CD8<sup>+</sup> T cell numbers. The highest increase (>50-fold) is found in the blood circulation. Compartmental analysis of exhausted T cell subsets shows that primarily undifferentiated, stem-like, tumor-specific CD8< ...[more]

PMID: 37045833

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Project description:BackgroundThis study aimed to explore the potentially predictive role and dynamic changes of immune checkpoints on T cell subsets in patients with breast cancer receiving neoadjuvant chemotherapies.MethodsFluorescent multiplex immunohistochemistry (mIHC) was used to stain CD4, CD8, PD1, TIM3, and cytokeratins simultaneously in paired breast cancer samples before and after neoadjuvant therapies (NAT) in a prospective cohort (n = 50). Singleplex IHC was conducted to stain for CD3 in 100 cases with inclusion of extra retrospective 50 cases. Cell levels were correlated with clinicopathological parameters and pathological complete response (pCR).ResultsIn pretreatment tumors, the percentages of infiltrating CD8+ , PD1+ , PD1+ CD8+ , and the ratio of PD1+ CD8+ /CD8+ cells, were higher in pCR than non-pCR patients in either the stromal or intratumoral area, but PD1+ CD4+ , TIM3+ CD4+ , TIM3+ CD8+ cells and CD4+ /CD8+ ratio was not. Multivariate analyses showed that the percentage of intratumoral CD8+ cells (OR, 1.712; 95% CI: 1.052-2.786; P = 0.030) and stromal PD1+ CD8+ /CD8+ ratio (OR, 1.109; 95% CI: 1.009-1.218; P = 0.032) were significantly associated with pCR. Dynamically, reduction in the percentages of PD1+ , CD8+ and PD1+ CD8+ cells after therapy strongly correlated with pCR. Notably, incremental percentages of PD1+ CD8+ cells, rather than TIM3+ CD8+ , were shown in tumors from non-pCR patients after NAT. CD3 staining confirmed the percentage of T cells were associated with pCR.ConclusionsPD1+ CD8+ rather than TIM3+ CD8+ cells are main predictive components within tumor-infiltrating T cells in NAT breast cancer patients. Dynamically incremental levels of PD1+ CD8+ cells occurred in non-pCR cases after NAT, suggesting the combination of chemotherapy with PD1 inhibition might benefit these patients.Key pointsSIGNIFICANT FINDINGS OF THE STUDY: PD1+ CD8+ , rather than TIM3+ CD8+ , T cells are the main component to predict the response of neoadjuvant therapies in breast cancer.What this study addsIncremental levels of PD1+ CD8+ T cells in non-pCR post-NAT tumors suggest PD1 inhibition might benefit in the neoadjuvant setting.

Project description:Background: Immune checkpoint blockers (ICBs) are revolutionized therapeutic strategies for cancer, but most patients with solid neoplasms remain resistant to ICBs, partly because of the difficulty in reversing the highly immunosuppressive tumor microenvironment (TME). Exploring the strategies for tumor immunotherapy is highly dependent on the discovery of molecular mechanisms of tumor immune escape and potential therapeutic target. Krüppel-like Factor 5 (KLF5) is a cell-intrinsic oncogene to promote tumorigenesis. However, the cell-extrinsic effects of KLF5 on suppressing the immune response to cancer remain unclear. Methods: We analyzed the immunosuppressive role of KLF5 in mice models transplanted with KLF5-deleted/overexpressing tumor cells. We performed RNA sequencing, immunohistochemistry, western blotting, real time-PCR, ELISA, luciferase assay, chromatin immunoprecipitation (ChIP), and flow cytometry to demonstrate the effects of KLF5 on CD8+ T cell infiltration and related molecular mechanism. Single-cell RNA sequencing and spatial transcriptomics analysis were applied to further decipher the association between KLF5 expression and infiltrating immune cells. The efficacy of KLF5/COX2 inhibitors combined with anti-programmed cell death protein 1 (anti-PD1) therapy were explored in pre-clinical models. Finally, a gene-expression signature depending on KLF5/COX2 axis and associated immune markers was created to predict patient survival. Results: KLF5 inactivation decelerated basal-like breast tumor growth in a CD8+ T-cell-dependent manner. Transcriptomic profiling revealed that KLF5 loss in tumors increases the number and activated function of T lymphocytes. Mechanistically, KLF5 binds to the promoter of the COX2 gene and promotes COX2 transcription; subsequently, KLF5 deficiency decreases prostaglandin E2 (PGE2) release from tumor cells by reducing COX2 expression. Inhibition of the KLF5/COX2 axis increases the number and functionality of intratumoral antitumor T cells to synergize the antitumorigenic effects of anti-PD1 therapy. Analysis of patient datasets at single-cell and spatial resolution shows that low expression of KLF5 is associated with an immune-supportive TME. Finally, we generate a KLF5/COX2-associated immune score (KC-IS) to predict patient survival. Conclusions: Our results identified a novel mechanism responsible for KLF5-mediated immunosuppression in TME, and targeting the KLF5/COX2/PGE2 axis is a critical immunotherapy sensitizer.

Dataset Information

Expansion of circulating stem-like CD8⁺ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

Publications

Expansion of circulating stem-like CD8<sup>+</sup> T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

Similar Datasets

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Dataset Information

Expansion of circulating stem-like CD8+ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

Publications

Expansion of circulating stem-like CD8<sup>+</sup> T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Expansion of circulating stem-like CD8⁺ T cells by adding CD122-directed IL-2 complexes to radiation and anti-PD1 therapies in mice.