Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies - PubMed (original) (raw)
Radiotherapy increases the permissiveness of established mammary tumors to rejection by immunomodulatory antibodies
Inge Verbrugge et al. Cancer Res. 2012.
Abstract
It is becoming increasingly evident that radiotherapy may benefit from coincident or subsequent immunotherapy. In this study, we examined whether the antitumor effects of radiotherapy, in established triple-negative breast tumors could be enhanced with combinations of clinically relevant monoclonal antibodies (mAb), designed to stimulate immunity [anti-(α)-CD137, α-CD40] or relieve immunosuppression [α-programmed death (PD)-1]. While the concomitant targeting of the costimulatory molecules CD137 and CD40 enhanced the antitumor effects of radiotherapy and promoted the rejection of subcutaneous BALB/c-derived 4T1.2 tumors, this novel combination was noncurative in mice bearing established C57BL/6-derived AT-3 tumors. We identified PD-1 signaling within the AT-3 tumors as a critical limiting factor to the therapeutic efficacy of α-CD137 therapy, alone and in combination with radiotherapy. Strikingly, all mice bearing established orthotopic AT-3 mammary tumors were cured when α-CD137 and α-PD-1 mAbs were combined with single- or low-dose fractionated radiotherapy. CD8+ T cells were essential for curative responses to this combinatorial regime. Interestingly, CD137 expression on tumor-associated CD8+ T cells was largely restricted to a subset that highly expressed PD-1. These CD137+PD-1High CD8+ T cells, persisted in irradiated AT-3 tumors, expressed Tim-3, granzyme B and Ki67 and produced IFN-γ ex vivo in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation. Notably, radiotherapy did not deplete, but enriched tumors of functionally active, tumor-specific effector cells. Collectively, these data show that concomitant targeting of immunostimulatory and inhibitory checkpoints with immunomodulatory mAbs can enhance the curative capacity of radiotherapy in established breast malignancy.
©2012 AACR.
Similar articles
- Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules.
Takeda K, Kojima Y, Uno T, Hayakawa Y, Teng MW, Yoshizawa H, Yagita H, Gejyo F, Okumura K, Smyth MJ. Takeda K, et al. J Immunol. 2010 May 15;184(10):5493-501. doi: 10.4049/jimmunol.0903033. Epub 2010 Apr 16. J Immunol. 2010. PMID: 20400706 - Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation.
Kim JA, Averbook BJ, Chambers K, Rothchild K, Kjaergaard J, Papay R, Shu S. Kim JA, et al. Cancer Res. 2001 Mar 1;61(5):2031-7. Cancer Res. 2001. PMID: 11280763 - Induction of therapeutic T-cell immunity by tumor targeting with soluble recombinant B7-immunoglobulin costimulatory molecules.
Moro M, Gasparri AM, Pagano S, Bellone M, Tornaghi P, Veglia F, Corti A, Casorati G, Dellabona P. Moro M, et al. Cancer Res. 1999 Jun 1;59(11):2650-6. Cancer Res. 1999. PMID: 10363988 - Immunotherapy with agonistic anti-CD137: two sides of a coin.
Sun Y, Chen JH, Fu Y. Sun Y, et al. Cell Mol Immunol. 2004 Feb;1(1):31-6. Cell Mol Immunol. 2004. PMID: 16212918 Review. - Clinical experiences with anti-CD137 and anti-PD1 therapeutic antibodies.
Ascierto PA, Simeone E, Sznol M, Fu YX, Melero I. Ascierto PA, et al. Semin Oncol. 2010 Oct;37(5):508-16. doi: 10.1053/j.seminoncol.2010.09.008. Semin Oncol. 2010. PMID: 21074066 Review.
Cited by
- Targeted spatial proteomic analysis of CD8+ T- and myeloid cells in tonsillar cancer.
Altunbulakli C, Jimenez DG, Askmyr D, Sobti A, Swoboda S, Greiff L, Lindstedt M. Altunbulakli C, et al. Front Oncol. 2023 Nov 17;13:1253418. doi: 10.3389/fonc.2023.1253418. eCollection 2023. Front Oncol. 2023. PMID: 38044986 Free PMC article. - Initial analysis of the synergy of programmed cell death-1 (PD-1) inhibitor and concurrent chemoradiotherapy treatment for recurrent/metastatic head and neck squamous cell carcinoma patients.
Li L, Chen L, Yan L, Guo Y, Li F, Fan M, Lan M, Lai X, Zhou J, Huang Y, Xu P, Lang J, Feng M. Li L, et al. Radiat Oncol. 2023 Jul 4;18(1):109. doi: 10.1186/s13014-023-02310-8. Radiat Oncol. 2023. PMID: 37403098 Free PMC article. - Chemotherapy-induced metastasis: molecular mechanisms and clinical therapies.
Su JX, Li SJ, Zhou XF, Zhang ZJ, Yan Y, Liu SL, Qi Q. Su JX, et al. Acta Pharmacol Sin. 2023 Sep;44(9):1725-1736. doi: 10.1038/s41401-023-01093-8. Epub 2023 May 11. Acta Pharmacol Sin. 2023. PMID: 37169853 Free PMC article. Review. - Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer.
Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Ren SN, et al. World J Gastroenterol. 2023 Apr 7;29(13):1911-1941. doi: 10.3748/wjg.v29.i13.1911. World J Gastroenterol. 2023. PMID: 37155531 Free PMC article. Review. - Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy.
Sadeghirad H, Liu N, Monkman J, Ma N, Cheikh BB, Jhaveri N, Tan CW, Warkiani ME, Adams MN, Nguyen Q, Ladwa R, Braubach O, O'Byrne K, Davis M, Hughes BGM, Kulasinghe A. Sadeghirad H, et al. Front Immunol. 2023 Apr 3;14:1135489. doi: 10.3389/fimmu.2023.1135489. eCollection 2023. Front Immunol. 2023. PMID: 37153589 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
Miscellaneous