Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses

Kwan, Byron H.; Zhu, Eric F.; Tzeng, Alice; Sugito, Harun R.; Eltahir, Ahmed; Ma, Botong; Delaney, Mary K.; Murphy, Patrick A.; Kauke, Monique J.; Angelini, Alessandro; Momin, Noor; Mehta, Naveen K.; Maragh, Alecia M.; Hynes, Richard O.; Dranoff, Glenn; Cochran, Jennifer R.; Wittrup, K. Dane

doi:10.1084/jem.20160831

Cited by 42 publications

(30 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to their role in primary tumor growth, integrins are also important mediators of metastasis 28 . They are involved in multiple steps that help in tumor spread: (i) degradation of the basement membrane barrier for tumor cells, 29‐35 (ii) angiogenesis for tumor survival at the primary site, 36‐39 (iii) as integral components of exosomes (small extracellular molecules detached from the primary tumor into the circulation), 40‐43 (iv) intravasation of tumor cells into the circulation, 36 and (v) implantation at the metastatic niche 44,45 …”

Section: Integrin Role In Primary Tumor Aggressivenessmentioning

confidence: 99%

The role of integrins in melanoma: a review

et al. 2020

View full text Add to dashboard Cite

Integrins are the major family of cell adhesion receptors in humans and essential for a wide range of normal physiology, including formation and maintenance of tissue structure integrity, cell migration, proliferation, and differentiation. Integrins also play a prominent role in tumor growth and metastasis. Translational research has tried to define the contribution of integrins to the phenotypic aggressiveness of melanoma because such knowledge is clinically useful. For example, differential expression of integrins in primary cutaneous melanoma can be used to distinguish indolent from aggressive, prometastatic melanoma.Recent studies have shown that gene expression-based testing of patient-derived melanoma tissue is feasible, and molecular tests may fully replace interventional surgical methods such as sentinel lymph node biopsies in the future. Because of their central role in mediating invasion and metastasis, integrins are likely to be useful biomarkers. Integrins are also attractive candidate targets for interventional therapy. This article focuses on the role of integrins in melanoma and highlights recent advances in the field of translational research.

show abstract

Section: Integrin Role In Primary Tumor Aggressivenessmentioning

confidence: 99%

The role of integrins in melanoma: a review

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The same toxicity trends occurred in a different tumor model and in two different mouse strains. In the MC38 colon carcinoma model, toxicity was reduced and efficacy was maintained when eIL2 was given concurrently with IFNα, following treatment with an antibody-like construct (2.5F-Fc) that targets integrins overexpressed on many mouse and human tumors, 30 (Figure 1(d,e). Weight loss curves over time ( Figure S2a) as well as individual tumor area curves ( Figure S2b-f) support the summarized weight loss and survival results.…”

Section: Resultsmentioning

confidence: 99%

Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models

et al. 2019

Self Cite

View full text Add to dashboard Cite

2019) Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models, OncoImmunology, 8:5, e1558678, ABSTRACTIn combination cancer immunotherapies, consideration should be given to designing treatment schedules that harmonize with the immune system's natural timing. An efficacious temporally programmed combination therapy of extended half-life interleukin 2 (eIL2), tumor targeting antibody, and interferon (IFN) α was recently reported; however, tumor-ablative efficacy was associated with significant toxicity. In the current work, altering the order and timing of the three agents is shown to decouple toxicity from efficacy. Delaying the administration of eIL2 to be concurrent with or after IFNα eliminates toxicity without affecting efficacy in multiple syngeneic tumor models and mouse strains. The toxicity resulting from eIL2 administration before IFNα is dependent on multiple systemic inflammatory cytokines including IL6, IL10, IFNγ, and tumor necrosis factor α. Natural killer (NK) cells are the main cellular contributor to toxicity, but are not essential for tumor control in this system. When pre-conditioned with eIL2, splenic NK cells became hyper-activated and upregulate IFNα signaling proteins that cause an excessive, toxic response to subsequent IFNα exposure. This work illustrates an example where accounting for the temporal dynamics of the immune system in combination therapy treatment schedule can favorably decouple efficacy and toxicity. ARTICLE HISTORY

show abstract

“…Despite these successes, development of multifunctional small molecule integrin antagonists that maintain high affinity and suitable pharmacokinetic properties remains a challenge (Nero et al, 2014). The engineered knottin miniproteins 2.5D and 2.5F have a number of advantages over small molecules and short peptides including exceptional structural stability, high affinity, and multispecificity to a number of tumor-associated integrins (Kimura et al, 2009b;Kwan et al, 2017). Their amenability to large-scale synthesis or recombinant expression as fusion proteins in E. coli or yeast provides a manufacturing advantage over monoclonal antibodies.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Agthoven

Shams²,

Cochran

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Integrins αVβ3 and α5β1 play critical roles in tumor survival, invasion, metastasis, and angiogenesis and are validated targets for cancer therapy and molecular imaging. Increasing evidence suggests that targeting both integrins simultaneously with antagonists is more effective in cancer therapy because of concerns about resistance and paradoxical promotion of tumor growth with use of agents highly selective for a single integrin. Engineered Arg-Gly-Asp (RGD)containing 3.5 kDa cysteine-knot proteins (knottins 2.5F and 2.5D) are attractive drug candidates due to their exceptional structural stability and high affinity binding to certain integrins. 2.5F binds both αVβ3 and α5β1, whereas 2.5D is αVβ3-selective. To elucidate the structural basis of integrin selection, we determined the structures of 2.5F and 2.5D both as apo-proteins and in complex with αVβ3. These data, combined with MD simulations and mutational studies, revealed a critical role of two αVβ3-specific residues in the vicinity of the metal ion dependent adhesion site (MIDAS) in promoting an αVβ3-induced fit of 2.5D. In contrast, conformational selection accounted for the specificity of 2.5F to both integrins. These data provide new insights into the structural basis of integrin-ligand binding specificity, and could help in development of integrin-targeted therapeutics.

show abstract

Integrin-targeted cancer immunotherapy elicits protective adaptive immune responses

Abstract: Integrin targeting for cancer has primarily focused on antagonizing integrin function, which has been clinically ineffective to date. In this study, Kwan et al. repurpose integrins as a beacon for recruiting immune effector functions to bolster current cancer immunotherapy approaches.

Cited by 42 publications

References 46 publications

The role of integrins in melanoma: a review

The role of integrins in melanoma: a review

Order of administration of combination cytokine therapies can decouple toxicity from efficacy in syngeneic mouse tumor models

Structural basis of the differential binding of engineered knottins 2.5F and 2.5D to integrins αVβ3 and α5β1

Contact Info

Product

Resources

About