Immunotherapy with a sting

doi:10.1126/science.abc6622

GSTDTAP > 气候变化

DOI	10.1126/science.abc6622
	Immunotherapy with a sting
	Thomas F. Gajewski; Emily F. Higgs
	2020-08-21
发表期刊	Science
出版年	2020
英文摘要	Tumor antigen-specific CD8+ T cells are a critical component of the antitumor immune response. Many cancer patients display evidence of an endogenous T cell response against their tumors, yet fail to eliminate tumors unaided. The failure of spontaneous immune-mediated tumor rejection is thought to be partially due to the action of negative regulatory mechanisms (immune checkpoints) that inhibit key functional properties of tumor-infiltrating T cells ([ 1 ][1]). Checkpoint blockade immunotherapies have demonstrated notable therapeutic success by overcoming tumor-induced T cell inhibition; however, their efficacy is poor when patients lack evidence of a spontaneous T cell response ([ 2 ][2], [ 3 ][3]). Innate immune agonists may promote priming and recruitment of tumor-specific CD8+ T cells and are gaining traction as a cancer immunotherapy approach. On page 935 and 993 of this issue, Pan et al. ([ 4 ][4]) and Chin et al. ([ 5 ][5]), respectively, describe innate immune agonists that show antitumor activity in preclinical cancer models. Antibodies targeting the immune checkpoint receptor, programmed cell death protein 1 (PD-1), or its major ligand, PD-L1, have been approved by the U.S. Food and Drug Administration for clinical use in ∼15 different cancer entities ([ 6 ][6]). Clinical benefit has been correlated with the presence of an activated T cell gene signature prior to treatment ([ 2 ][2]), and following anti–PD-1 administration, a marked expansion of tumor-infiltrating CD8+ T cells has been observed ([ 3 ][3]). Despite clinical successes, a major subset of cancer patients lack sufficient T cell inflammation, and these patients generally do not respond to checkpoint blockade immunotherapy ([ 7 ][7]). It is thought that triggering productive T cell–based inflammation within the tumor microenvironment may offer the potential to expand the fraction of patients benefiting from anti–PD-1 treatment and other immunotherapies. One strategy toward this goal has been to gain an understanding of the fundamental mechanistic steps involved in spontaneous T cell activation and tumor infiltration when it does occur, with the aim of mimicking or reproducing those steps in the cases when it does not occur. In general, an adaptive immune response (i.e., induction of a T cell or antibody response) first requires activation of the innate immune system, which nonspecifically signals the presence of “danger” or an outside threat. Preclinical tumor models revealed that endogenous CD8+ T cell priming (activation) by innate antigen-presenting cells (APCs) was markedly reduced in mice deficient for STING (stimulator of interferon genes) ([ 8 ][8]). Mice lacking STING also showed reduced cytokine production, including interferon-β (IFN-β), in response to tumor implantation and failed to reject highly immunogenic tumors. These defects were not observed in mice deficient in other innate immune pathways, such as specific Toll-like receptors (TLRs). The STING pathway is a cytosolic DNA-sensing pathway, and tumor-derived DNA could be found within the cytosol of tumor-infiltrating APCs. Cytosolic DNA is detected within cells when it binds to cGAS [cyclic guanosine monophosphate (GMP)–adenosine monophosphate (AMP) (cGAMP) synthase], which generates cGAMP, which in turn engages and activates STING ([ 9 ][9]). Signaling downstream of STING leads to APC activation and inflammatory cytokine production, which subsequently promotes T cell priming and recruitment ([ 10 ][10]). Together, these observations led to the hypothesis that exogenous agonists of the STING pathway may have the potential to trigger de novo innate immune activation, leading to an adaptive immune response that can control tumor growth alone or in combination with checkpoint blockade immunotherapy. The first STING agonist investigated for immunotherapy was the molecule DMXAA, which had antitumor activity in preclinical models and was subsequently determined to interact with the mouse STING molecule but not human STING ([ 11 ][11]). The first generation of human STING agonists, including MIW815 (ADU-S100) and MK-1454, have been investigated in early-phase clinical trials alone and in combination with anti–PD-1. So far, some clinical responses to these agonists have been observed, but only in a minority of patients ([ 12 ][12], [ 13 ][13]). Several biological considerations are being explored to understand mechanisms of response versus resistance. These include deciphering which immune cells in the tumor microenvironment must be present for STING agonists to induce downstream T cell priming, understanding the optimal dose and schedule of STING agonists to avoid overstimulation and negative regulation, and identifying predictive biomarkers for clinical activity. The metabolic instability of cyclic dinucleotide–based STING agonists requires them to be administered intratumorally. The constraint for intratumoral administration itself has limitations, because physical issues such as increased intratumoral pressure, restraints on diffusion of the injected agent, and the impossibility of injecting all metastatic lesions in an advanced cancer patient are all potential barriers to therapeutic efficacy. A small number of intravenous STING agonists have begun evaluation in clinical trials (NCT03843359, NCT04420884, and NCT04096638), and the next focus of STING agonist development will likely be on agonists formulated for systemic administration, such as those reported by Pan et al. and Chin et al. (see the figure). Clinical development of systemically administered STING agonists needs to account for several important considerations. One is that systemic administration may lead to greater toxicity, because engaging APCs outside the tumor microenvironment may release high amounts of IFN-β and other inflammatory cytokines. Chin et al. report that efficacious doses of SR-717 led to significantly lower concentrations of serum IFN-β than another recently developed systemic STING agonist, diABZI-2. Systemic administration of diABZI-2 also promoted tumor control; however, diABZI-2 stabilizes STING in its open conformation, similar to the bacterial product cyclic di-GMP but unlike endogenous cGAMP ([ 14 ][14]). The agonists presented by Pan et al. and Chin et al. both stabilize the closed conformation of STING. Further study is necessary to tease apart the biological consequences of stabilizing STING in its open versus closed conformations. The MSA-2 compound described by Pan et al. also demonstrated limited toxicity in mice despite systemic administration, owing to its preferential bioactivity within the acidic milieu of the tumor microenvironment. ![Figure][15] New innate immune agonists The non-nucleotide stimulator of interferon genes (STING) agonists MSA-2 and SR-717 reported by Pan et al. and Chin et al. , respectively, stabilize STING in its closed conformation. STING activation induces downstream signaling events that culminate in the expression of inflammatory cytokines such as interferon-β (IFN-β) and interleukin-6 (IL-6). Secretion of these cytokines in the tumor microenvironment promotes the maturation and activation of cDC1 dendritic cells, which then promote antitumor immunity by priming tumor antigen–specific CD8+ T cells in the tumor-draining lymph node. GRAPHIC: MELISSA THOMAS BAUM/ SCIENCE A second important consideration is the effect of systemic STING agonists on specific immune cell subpopulations. Chin et al. noted that SR-717 induced expression of the immunosuppressive molecules PD-L1 and indoleamine 2,3-dioxygenase 1 (IDO1) in primary human peripheral blood mononuclear cells in vitro. Additionally, intraperitoneal injection of SR-717 in a melanoma mouse model led to increased PD-L1 expression on CD11c+CD8− dendritic cells but not on CD8+ dendritic cells isolated from tumor-draining lymph nodes. Although CD8+ dendritic cells are thought to be the key APC subset for inducing tumor-specific CD8+ T cell priming, it is notable that SR-717 affected these dendritic cell subtypes differently. Further characterization of the ways by which STING agonists induce both stimulatory and suppressive events in relevant cell subpopulations within the tumor microenvironment will be critical. Antitumor efficacy of SR-717 was not improved by either anti–PD-1 or anti–PD-L1 treatment in a mouse model of melanoma, which is in contrast to MSA-2, which did show improved tumor shrinkage when combined with anti–PD-1 therapy. These differences could be due to different molecular properties of these STING agonists, differences in dose and schedule of administration in combination with immune checkpoint blockade, or distinctions between the experimental models used. A third consideration for clinical development is the dose and schedule of administered drug. These need to be optimized carefully, because systemic administration also may give rise to a bell-shaped efficacy curve. Probing pharmacodynamic endpoints within the tumor microenvironment associated with activity should guide selection of therapeutic dosing. Fourth, the consideration of which tumor types and which patients have the potential to respond to these agents also needs to be addressed, so predictive biomarkers for appropriate patient selection also need to be pursued. A final consideration is that other innate immune agonists are advancing in clinical development, including agents targeting TLR pathways, such as TLR9 ([ 15 ][16]). Understanding which innate immune pathway is functionally relevant in distinct patient populations will be paramount toward optimization of innate immune agonist combinations with existing immunotherapies. The compounds reported by Chin et al. and Pan et al. illustrate how distinctive molecular properties of STING agonists can determine the balance of activity in the tumor versus systemically. Non-nucleotide small-molecule STING agonists that can be administered systemically may represent an attractive approach for targeting this pathway and have the potential to transform the therapeutic landscape once optimized. 1. [↵][17]1. G. J. Freeman et al ., J. Exp. Med. 192, 1027 (2000). [OpenUrl][18][Abstract/FREE Full Text][19] 2. [↵][20]1. M. Ayers et al ., J. Clin. Invest. 127, 2930 (2017). [OpenUrl][21][CrossRef][22][PubMed][23] 3. [↵][24]1. P. C. Tumeh et al ., Nature 515, 568 (2014). [OpenUrl][25][CrossRef][26][PubMed][27][Web of Science][28] 4. [↵][29]1. B.-S. Pan et al ., Science 369, aba6098 (2020). [OpenUrl][30] 5. [↵][31]1. E. N. Chin et al ., Science 369, 993 (2020). [OpenUrl][32][Abstract/FREE Full Text][33] 6. [↵][34]1. R. K. Vaddepally, 2. P. Kharel, 3. R. Pandey, 4. R. Garje, 5. A. B. Chandra , Cancers (Basel) 12, 738 (2020). [OpenUrl][35] 7. [↵][36]1. J. A. Trujillo, 2. R. F. Sweis, 3. R. Bao, 4. J. J. Luke , Cancer Immunol. Res. 6, 990 (2018). [OpenUrl][37][Abstract/FREE Full Text][38] 8. [↵][39]1. S.-R. Woo et al ., Immunity 41, 830 (2014). [OpenUrl][40][CrossRef][41][PubMed][42] 9. [↵][43]1. L. Sun, 2. J. Wu, 3. F. Du, 4. X. Chen, 5. Z. J. Chen , Science 339, 786 (2013). [OpenUrl][44][Abstract/FREE Full Text][45] 10. [↵][46]1. L. Corrales et al ., Cell Rep. 11, 1018 (2015). [OpenUrl][47][CrossRef][48][PubMed][49] 11. [↵][50]1. J. Conlon et al ., J. Immunol. 190, 5216 (2013). [OpenUrl][51][Abstract/FREE Full Text][52] 12. [↵][53]1. F. Meric-Bernstam et al ., J. Clin. Oncol. 37 (15_suppl.), 2507 (2019). [OpenUrl][54] 13. [↵][55]1. K. J. Harrington et al ., Ann. Oncol. 29, viii712 (2018). [OpenUrl][56][CrossRef][57] 14. [↵][58]1. J. M. Ramanjulu et al ., Nature 564, 439 (2018). [OpenUrl][59] 15. [↵][60]1. M. Reilley et al ., J. Clin. Oncol. 37 (15_suppl.), TPS2669 (2019). [OpenUrl][61] Acknowledgments: The authors are funded by the National Institutes of Health (grants F30CA250255 to E.F.H. and R35CA210098 to T.F.G.). T.F.G. reports a licensing agreement and receives research support and consultancy fees from Aduro Biotech. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-6 [7]: #ref-7 [8]: #ref-8 [9]: #ref-9 [10]: #ref-10 [11]: #ref-11 [12]: #ref-12 [13]: #ref-13 [14]: #ref-14 [15]: pending:yes [16]: #ref-15 [17]: #xref-ref-1-1 "View reference 1 in text" [18]: {openurl}?query=rft.jtitle%253DJ.%2BExp.%2BMed.%26rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.192.7.1027%26rft_id%253Dinfo%253Apmid%252F11015443%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [19]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamVtIjtzOjU6InJlc2lkIjtzOjEwOiIxOTIvNy8xMDI3IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzY5LzY1MDYvOTIxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [20]: #xref-ref-2-1 "View reference 2 in text" [21]: {openurl}?query=rft.jtitle%253DJ.%2BClin.%2BInvest.%26rft.volume%253D127%26rft.spage%253D2930%26rft_id%253Dinfo%253Adoi%252F10.1172%252FJCI91190%26rft_id%253Dinfo%253Apmid%252F28650338%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [22]: /lookup/external-ref?access_num=10.1172/JCI91190&link_type=DOI [23]: /lookup/external-ref?access_num=28650338&link_type=MED&atom=%2Fsci%2F369%2F6506%2F921.atom [24]: #xref-ref-3-1 "View reference 3 in text" [25]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D515%26rft.spage%253D568%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature13954%26rft_id%253Dinfo%253Apmid%252F25428505%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [26]: /lookup/external-ref?access_num=10.1038/nature13954&link_type=DOI [27]: /lookup/external-ref?access_num=25428505&link_type=MED&atom=%2Fsci%2F369%2F6506%2F921.atom [28]: /lookup/external-ref?access_num=000346247600054&link_type=ISI [29]: #xref-ref-4-1 "View reference 4 in text" [30]: {openurl}?query=rft.jtitle%253DScience%26rft.volume%253D369%26rft.spage%253Daba6098%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [31]: #xref-ref-5-1 "View reference 5 in text" [32]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DChin%26rft.auinit1%253DE.%2BN.%26rft.volume%253D369%26rft.issue%253D6506%26rft.spage%253D993%26rft.epage%253D999%26rft.atitle%253DAntitumor%2Bactivity%2Bof%2Ba%2Bsystemic%2BSTING-activating%2Bnon-nucleotide%2BcGAMP%2Bmimetic%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.abb4255%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [33]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNjkvNjUwNi85OTMiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwNi85MjEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [34]: #xref-ref-6-1 "View reference 6 in text" [35]: {openurl}?query=rft.jtitle%253DCancers%2B%2528Basel%2529%26rft.volume%253D12%26rft.spage%253D738%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [36]: #xref-ref-7-1 "View reference 7 in text" [37]: {openurl}?query=rft.jtitle%253DCancer%2BImmunology%2BResearch%26rft.stitle%253DCancer%2BImmunol%2BRes%26rft.aulast%253DTrujillo%26rft.auinit1%253DJ.%2BA.%26rft.volume%253D6%26rft.issue%253D9%26rft.spage%253D990%26rft.epage%253D1000%26rft.atitle%253DT%2BCell-Inflamed%2Bversus%2BNon-T%2BCell-Inflamed%2BTumors%253A%2BA%2BConceptual%2BFramework%2Bfor%2BCancer%2BImmunotherapy%2BDrug%2BDevelopment%2Band%2BCombination%2BTherapy%2BSelection%26rft_id%253Dinfo%253Adoi%252F10.1158%252F2326-6066.CIR-18-0277%26rft_id%253Dinfo%253Apmid%252F30181337%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [38]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FuaW1tIjtzOjU6InJlc2lkIjtzOjc6IjYvOS85OTAiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwNi85MjEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [39]: #xref-ref-8-1 "View reference 8 in text" [40]: {openurl}?query=rft.jtitle%253DImmunity%26rft.volume%253D41%26rft.spage%253D830%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.immuni.2014.10.017%26rft_id%253Dinfo%253Apmid%252F25517615%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [41]: /lookup/external-ref?access_num=10.1016/j.immuni.2014.10.017&link_type=DOI [42]: /lookup/external-ref?access_num=25517615&link_type=MED&atom=%2Fsci%2F369%2F6506%2F921.atom [43]: #xref-ref-9-1 "View reference 9 in text" [44]: {openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1232458%26rft_id%253Dinfo%253Apmid%252F23258413%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [45]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMzkvNjEyMS83ODYiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwNi85MjEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [46]: #xref-ref-10-1 "View reference 10 in text" [47]: {openurl}?query=rft.jtitle%253DCell%2BRep.%26rft.volume%253D11%26rft.spage%253D1018%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.celrep.2015.04.031%26rft_id%253Dinfo%253Apmid%252F25959818%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [48]: /lookup/external-ref?access_num=10.1016/j.celrep.2015.04.031&link_type=DOI [49]: /lookup/external-ref?access_num=25959818&link_type=MED&atom=%2Fsci%2F369%2F6506%2F921.atom [50]: #xref-ref-11-1 "View reference 11 in text" [51]: {openurl}?query=rft.jtitle%253DJ.%2BImmunol.%26rft_id%253Dinfo%253Adoi%252F10.4049%252Fjimmunol.1300097%26rft_id%253Dinfo%253Apmid%252F23585680%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [52]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiamltbXVub2wiO3M6NToicmVzaWQiO3M6MTE6IjE5MC8xMC81MjE2IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzY5LzY1MDYvOTIxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [53]: #xref-ref-12-1 "View reference 12 in text" [54]: {openurl}?query=rft.jtitle%253DJ.%2BClin.%2BOncol.%26rft.volume%253D37%26rft.spage%253D2507%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [55]: #xref-ref-13-1 "View reference 13 in text" [56]: {openurl}?query=rft.jtitle%253DAnn.%2BOncol.%26rft.volume%253D29%26rft.spage%253Dviii712%26rft_id%253Dinfo%253Adoi%252F10.1093%252Fannonc%252Fmdy424.015%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [57]: /lookup/external-ref?access_num=10.1093/annonc/mdy424.015&link_type=DOI [58]: #xref-ref-14-1 "View reference 14 in text" [59]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D564%26rft.spage%253D439%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [60]: #xref-ref-15-1 "View reference 15 in text" [61]: {openurl}?query=rft.jtitle%253DJ.%2BClin.%2BOncol.%26rft.volume%253D37%26rft.spage%253DTPS2669%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx
领域	气候变化 ; 资源环境
URL	查看原文
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/291206
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Thomas F. Gajewski,Emily F. Higgs. Immunotherapy with a sting[J]. Science,2020.
APA	Thomas F. Gajewski,&Emily F. Higgs.(2020).Immunotherapy with a sting.Science.
MLA	Thomas F. Gajewski,et al."Immunotherapy with a sting".Science (2020).