Nature Heavyweight: Bypass immune checkpoint IL-18BP restrictions, IL-18 immunotherapy progress again.

Cytokine is a secreted protein, which can be used in immunotherapy of tumor.however, its clinical application is limited due to its unsatisfactory specificity and toxicity.IL-18 is a member of IL-1 cytokine family and can activate innate lymphocytes and T cells.because IL-18 can induce the proliferation of immune cells and enhance their activity, its anti-tumor effect has been widely studied in recent years.on June 24, 2020, Aaron M. ring, Yale University School of medicine, published a research paper entitled "IL-18BP is a secret immune checkpoint and barrier to IL-18 immunity" online in nature.this study found that IL-18BP produced in tumor microenvironment (TME) can be used as a "secretory immune checkpoint" to limit the efficacy of IL-18 immunotherapy.therefore, the author designed a kind of IL-18 (decoy resistant IL-18, dr-18), which could not be inhibited by IL-18BP, and had significant antitumor effect.doi:10.1038/s41586-020-2422-6 The researchers found that IL-18R and IL-18BP were widely expressed in TME.to study its function, they transplanted MC38 tumor into wild-type C57BL / 6 mice or il18bp − / − mice and treated with mil-18 or vector.mil-18 had no effect on the tumor growth of wild-type mice, but could significantly inhibit the tumor growth of il18bp − / − mice.therefore, the authors believe that IL-18BP can be used as an immune checkpoint to block the function of IL-18.based on this, the researchers designed more than 250 million mil-18 mutants. Using yeast surface display technology, we used IL-18BP and IL-18R α to conduct directional selection and anti selection on them. Finally, we obtained the mutant that only combined with IL-18R α but had very low affinity to IL-18BP, namely dr-18.Image Source: the results of nature mouse colon cancer and melanoma models showed that the tumor inhibitory effect of dr-18 was better than that of IL-18 and PD-1 antibodies.the combination of dr-18 and PD-1 has the best curative effect, which can make most of the tumor completely subside in mice. However, dr-18 did not affect tumor growth in IL-18R knockout mice.so, how does dr-18 play a role in tumor immunotherapy? Antibody mediated depletion was studied.the results showed that depletion of CD8 + T cells and / or CD4 + T cells could inhibit the effect of dr-18 in mice models of colon cancer and melanoma.therefore, the antitumor effect of dr-18 is mediated by T cells. in order to further study the effect of dr-18 on TME, single cell RNA sequencing was performed on the above model. the results showed that the transcription level of effector molecules (Ifng, PRF1 and gzmB) in CD8 + T cells increased after dr-18 treatment, while CD8 + T cells showed depletion type T cells (Tex) after mil-18 or PBS treatment. in addition, dr-18 can effectively increase the number of stem cell like CD8 + T cells of TCF + and PD-1 + inside and outside the tumor, so as to play a lasting and effective immunotherapy effect. Image Source: nature. In addition, the analysis of NK1.1 + cell population showed that the number of NK cells increased after dr-18 treatment. in general, dr-18 can remodel TME, enhance the function of T cells, promote the proliferation of T cells, and promote the maturation and versatility of anti-tumor NK cells. the author's team designed the human dr-18 (hdr-18) in the same way. the results showed that hdr-18 was also tightly bound to IL-18R α (not IL-18BP), and could stimulate NF - κ B signal transduction without being inhibited by IL-18BP. and in human and rhesus monkey peripheral blood mononuclear cells, hdr-18 causes IFN - γ production. in general, this study demonstrates that IL-18BP plays a key role in tumor immunity as a secretory immune checkpoint to limit the efficacy of IL-18. the dr-18 designed by the researchers has the ability to act on CD8 + teff cells, stem cell like tcf1 + CD8 + T cells and NK cells, which provides a strong basis for the clinical development of dr-18 and other IL-18 receptor agonists. end reference: [1] IL-18BP is a secret immune checkpoint and barrier to IL-18 immunity