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459 NK cells activation and recruitment to irradiated tumors is increased in the presence of IL-15
  1. Maud Charpentier1,
  2. Karsten Pilones1,
  3. Elena Garcia-Martinez2 and
  4. Sandra Demaria1
  1. 1Weill Cornell Medicine, New York, NY, USA
  2. 2Hospital Universitario Morales Meseguer, Murcia, Spain


Background Focal radiotherapy (RT) promotes tumor infiltration by conventional dendritic cells type 1 (cDC1), an effect dependent on radiation’s ability to induce type I interferon (IFN-I) secretion. We recently demonstrated that peritumoral s.c. IL-15, while ineffective by itself, synergized with RT, inducing complete regression of the irradiated tumor and long-term protective memory in two murine carcinomas models (TSA, MCA-38) (1). These responses were abrogated in the absence of CD8 T cells or cDC1. Detailed investigations in the TSA model showed that, whereas IL-15 alone had no effects on cDC1, it did significantly increase intratumoral cDC1 numbers and expression of costimulatory molecules CD80 and CD86 induced by RT (1). In addition to CD8 T cells, IL-15 activates NK cells, which have also been implicated in cDC1 tumor recruitment (2). Thus, we hypothesized that NK cells may play a role in the synergy between radiation therapy and IL-15.

Methods To test this hypothesis, BALB/c mice were injected with TSA mammary carcinoma cells and treated with RT (8Gy X3) and daily subcutaneous injections of IL-15 (5µg). Tumors were excised at day 18 and analyzed by immunostaining for NKp46+ cells on tumor sections and flow cytometry after tumor dissociation.

Results The number of intra-tumoral NKp46+ NK cells was significantly higher (p<0.005) in mice treated with IL-15 as compared to control. Whereas RT itself had no effect, it further increased NK cell numbers above what was achieved by IL-15 alone (p<0.05). In addition, tumor infiltrating NK cells expressed higher levels of CD137/4-1 BB, an effect largely driven by IL-15. Finally, NK cells depletion by anti-asialo GM1 before initiation of the treatment abrogated the enhanced cDC1 infiltration in tumors of mice treated with RT + IL-15, and the therapeutic effect of the combination.

Conclusions Our results strongly suggest a role for NK cells in the anti-tumor immune response induced by the combination of RT and IL-15. We are currently working to confirm the role of NK cells by using a complementary approach of engineering TSA cells to overexpress CLEC2D/Clr-b, the ligand for the inhibitory NKR-P1 NK receptor (3,4). Data obtained will improve current knowledge about the interaction of RT with IL-15 and support a rationale strategy for translation to the clinic.


  1. Pilones KA, Charpentier M, Garcia-Martinez E, et al. Radiotherapy cooperates with IL15 to induce antitumor immune responses. Cancer Immunol Res 2020;8(8):1054–1063. doi:10.1158/2326-6066.CIR-19-0338

  2. Böttcher JP, Bonavita E, Chakravarty P, et al. NK Cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 2018;172(5):1022–1037.e14. doi:10.1016/j.cell.2018.01.004

  3. Carlyle JR, Jamieson AM, Gasser S, Clingan CS, Arase H, Raulet DH. Missing self-recognition of Ocil/Clr-b by inhibitory NKR-P1 natural killer cell receptors. Proc Natl Acad Sci U S A 2004;101(10):3527–3532. doi:10.1073/pnas.0308304101

  4. Williams KJ, Wilson E, Davidson CL, et al. Poxvirus infection-associated downregulation of C-type lectin-related-b prevents NK cell inhibition by NK receptor protein-1B. J Immunol 2012;188(10):4980–4991. doi:10.4049/jimmunol.1103425

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