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

Onyshchenko, Kateryna; Luo, Ren; Guffart, Elena; Gaedicke, Simone; Grosu, Anca‐Ligia; Firat, Elke; Niedermann, Gabriele

doi:10.1038/s41467-023-37825-x

Cited by 10 publications

(9 citation statements)

References 69 publications

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“…The combination of RT and modified IL-2 variants has achieved potent anti-cancer responses in both preclinical models as well as in clinical trials and is proving to be an efficacious therapeutic combination 32,33,60 . However, a majority of these IL-2 variants target the dimeric IL-2R to stimulate memory CD8 + T cells and avoid Treg expansion.…”

Section: Discussionmentioning

confidence: 99%

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IL-2 immunotherapy rescues irradiation-induced T cell exhaustionin vivo

Yong,

Telarovic,

Gregor

et al. 2024

Preprint

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Radiotherapy (RT) can stimulate anti-cancer T cell responses that target primary and distant tumors. In addition to antigen-mediated stimulation of effector T cells, signals from stimulatory cytokines, notably interleukin-2 (IL-2), are necessary for optimal T cell function and memory. However, timing and IL-2 receptor (IL-2R) bias of such signals are ill-defined. Using image-guided RT in a mouse colon cancer model, we observed that single high-dose (1 x 20 Gy) RT transiently upregulated IL-2Ra (CD25) on effector CD8+ T cells, facilitating the use of CD25-biased IL-2 immunotherapy. Timed administration of CD25-biased IL-2 treatment after RT favored the expansion of tumor-infiltrating CD8+ T cells over regulatory T cells and IL-2Rb (CD122)high CD8+ T cells, which resulted in comparable anti-tumor effects as with RT plus CD122-biased IL-2 immunotherapy. Moreover, intratumoral CD8+ T cells from animals receiving combined IL-2R-biased IL-2 and RT showed reduced signatures of T cell exhaustion. Finally, these combination treatments affected both primary irradiated and distant non-irradiated tumors, achieving durable responses. We demonstrate that timed and IL-2R subunit-biased IL-2 immunotherapy synergized with single high-dose RT to achieve potent anti-cancer immunity.

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Section: Discussionmentioning

confidence: 99%

“…Moreover, RT was combined with IL-2 variants that preferentially targeted effector immune cells or antigens present in the tumor microenvironment [30][31][32][33] . Although these studies demonstrated some efficacy of combined RT and IL-2 immunotherapy, it is unknown which IL-2R signals and bias combine best with which RT treatment scheme.…”

Section: Introductionmentioning

confidence: 99%

IL-2 immunotherapy rescues irradiation-induced T cell exhaustionin vivo

Yong,

Telarovic,

Gregor

et al. 2024

Preprint

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“… 532 However, several recent papers reported less terminal exhaustion, and expansion of stem-like and effector-like T cells upon treatment with IL-2 or IL-2 variants. 379 , 533 , 534 When recombinant wild-type IL-2 was combined with PD-1 blockade in the model of chronic lymphocytic choriomeningitis virus infection, even a deviation from the normal exhaustion program towards the formation of “better effectors” was observed and depended on IL-2 binding to CD25. 534 , 535 Similar observations were made in tumor models using an IL-2Rβγ-biased IL-2 derivative fused to an anti-PD-1 antibody.…”

Section: Cytokinesmentioning

confidence: 99%

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Yin,

Li,

Zhang

et al. 2024

Sig Transduct Target Ther

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Immunotherapy represented by anti-PD-(L)1 and anti-CTLA-4 inhibitors has revolutionized cancer treatment, but challenges related to resistance and toxicity still remain. Due to the advancement of immuno-oncology, an increasing number of novel immunoregulatory targets and mechanisms are being revealed, with relevant therapies promising to improve clinical immunotherapy in the foreseeable future. Therefore, comprehending the larger picture is important. In this review, we analyze and summarize the current landscape of preclinical and translational mechanistic research, drug development, and clinical trials that brought about next-generation pharmacological immunoregulatory anti-cancer agents and drug candidates beyond classical immune checkpoint inhibitors. Along with further clarification of cancer immunobiology and advances in antibody engineering, agents targeting additional inhibitory immune checkpoints, including LAG-3, TIM-3, TIGIT, CD47, and B7 family members are becoming an important part of cancer immunotherapy research and discovery, as are structurally and functionally optimized novel anti-PD-(L)1 and anti-CTLA-4 agents and agonists of co-stimulatory molecules of T cells. Exemplified by bispecific T cell engagers, newly emerging bi-specific and multi-specific antibodies targeting immunoregulatory molecules can provide considerable clinical benefits. Next-generation agents also include immune epigenetic drugs and cytokine-based therapeutics. Cell therapies, cancer vaccines, and oncolytic viruses are not covered in this review. This comprehensive review might aid in further development and the fastest possible clinical adoption of effective immuno-oncology modalities for the benefit of patients.

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“…Moreover, TA-HEVs have recently been associated with a higher proportion of TCF1 + TIM3 - PD1 + stem-like exhausted CD8 + tumor-infiltrating lymphocytes (TILs) 28 . These TCF1 + PD1 + cells differentiate into the effector-like “transitory” CD101 - TIM3 + PD1 + subset originally described in the model of lymphocytic choriomeningitis virus (LCMV) 29 and later found in mouse tumor models 30 . Terminally differentiated exhausted T cells exhibit expression of CD101 and decreased cytokine production 29 - 31 .…”

Section: Introductionmentioning

confidence: 97%

“…Terminally differentiated exhausted T cells exhibit expression of CD101 and decreased cytokine production 29 - 31 . Non-terminally differentiated exhausted CD8 + T cells were reported to positively correlate with favorable anti-tumor response following immunotherapy 32 , 33 or radio/immunotherapy 30 , 34 , 35 .…”

Section: Introductionmentioning

confidence: 99%

Hypofractionated radiotherapy combined with lenalidomide improves systemic antitumor activity in mouse solid tumor models

Onyshchenko,

Luo,

Rao

et al. 2024

Theranostics

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Background: Hypofractionated radiotherapy (hRT) can induce a T cell-mediated abscopal effect on non-irradiated tumor lesions, especially in combination with immune checkpoint blockade (ICB). However, clinically, this effect is still rare, and ICB-mediated adverse events are common. Lenalidomide (lena) is an anti-angiogenic and immunomodulatory drug used in the treatment of hematologic malignancies. We here investigated in solid tumor models whether lena can enhance the abscopal effect in double combination with hRT. Methods: In two syngeneic bilateral tumor models (B16-CD133 melanoma and MC38 colon carcinoma), the primary tumor was treated with hRT. Lena was given daily for 3 weeks. Besides tumor size and survival, the dependence of the antitumor effects on CD8 + cells, type-I IFN signaling, and T cell costimulation was determined with depleting or blocking antibodies. Tumor-specific CD8 + T cells were quantified, and their differentiation and effector status were characterized by multicolor flow cytometry using MHC-I tetramers and various antibodies. In addition, dendritic cell (DC)-mediated tumor antigen cross-presentation in vitro and directly ex vivo and the composition of tumor-associated vascular endothelial cells were investigated. Results: In both tumor models, the hRT/lena double combination induced a significant abscopal effect. Control of the non-irradiated secondary tumor and survival were considerably better than with the respective monotherapies. The abscopal effect was strongly dependent on CD8 + cells and associated with an increase in tumor-specific CD8 + T cells in the non-irradiated tumor and its draining lymph nodes. Additionally, we found more tumor-specific T cells with a stem-like (TCF1 + TIM3 -PD1 + ) and a transitory (TCF1 -TIM3 + CD101 -PD1 + ) exhausted phenotype and more expressing effector molecules such as GzmB, IFNγ, and TNFα. Moreover, in the non-irradiated tumor, hRT/lena treatment also increased DCs cross-presenting a tumor model antigen. Blocking type-I IFN signaling, which is essential for cross-presentation, completely abrogated the abscopal effect. A gene expression analysis of bone marrow-derived DCs revealed that lena augmented the expression of IFN response genes and genes associated with differentiation, maturation (including CD70, CD83, and CD86), migration to lymph nodes, and T cell activation. Flow cytometry confirmed an increase in CD70 + CD83 + CD86 + DCs in both irradiated and abscopal tumors. Moreover, the hRT/lena-induced abscopal effect was diminished when these costimulatory molecules were blocked simultaneously using antibodies. In line with the enhanced infiltration by DCs and tumor-specific CD8 + T cells, including more stem-like cells, hRT/lena also increased tumor-associated high endothelial cells (TA-HECs) in the non-irradiated tumor.

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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

Cited by 10 publications

References 69 publications

IL-2 immunotherapy rescues irradiation-induced T cell exhaustionin vivo

IL-2 immunotherapy rescues irradiation-induced T cell exhaustionin vivo

Development of pharmacological immunoregulatory anti-cancer therapeutics: current mechanistic studies and clinical opportunities

Hypofractionated radiotherapy combined with lenalidomide improves systemic antitumor activity in mouse solid tumor models

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