Recruiting T cells in cancer immunotherapy

doi:10.1126/science.abd1329

GSTDTAP > 气候变化

DOI	10.1126/science.abd1329
	Recruiting T cells in cancer immunotherapy
	Kathryn E. Yost; Howard Y. Chang; Ansuman T. Satpathy
	2021-04-09
发表期刊	Science
出版年	2021
英文摘要	Immunotherapies that enhance the ability of the immune system to target cancer cells have proven effective in a variety of tumor types, yet clinical responses vary across patients and cancers. The most effective immunotherapies to date are immune checkpoint blocking antibodies, which target inhibitory surface receptors expressed by T cells, particularly programmed cell death 1 (PD-1). One of the few robust correlates of clinical response to PD-1 blockade is the presence of tumor-infiltrating T lymphocytes (TILs) prior to treatment, with immune-infiltrated tumors achieving better responses than “immunedesert” tumors ([ 1 ][1]). Therefore, it has been widely assumed that PD-1 blockade reinvigorates preexisting cells within the tumor microenvironment (TME). However, recent studies of T cell dynamics suggest that the T cell response to immune checkpoint blockade (ICB) may originate outside the tumor and rely on peripheral T cell recruitment. This has important implications for patient selection, predictive biomarkers, and design of combination treatment regimens. The site of ICB activity has historically been predicted from the expression pattern of the target inhibitory receptor and its ligand. The first immune checkpoint inhibitor that was approved for cancer targeted the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor, which is primarily expressed by CD4+ effector T cells and regulatory T cells (Tregs). Given that the CTLA-4 ligand, B7, is not expressed on malignant cells but rather on antigen-presenting cells (APCs) in the lymph node, CTLA-4 blockade was predicted to act on a lymph node–resident population of CD4+ T cells, which is subsequently recruited to the tumor. Indeed, studies in mouse models and patients have demonstrated that CTLA-4 blockade induces expansion of a subset of tumor-infiltrating CD4+ T cells expressing inducible T cell costimulator (ICOS), and increased ICOS+CD4+ T cell frequency following CTLA-4 blockade correlates with clinical response ([ 2 ][2]). Given its expression, CTLA-4 blockade has also been hypothesized to deplete intratumoral Tregs; however, this has not been consistently observed in patients ([ 2 ][2]). Several monoclonal antibodies targeting PD-1 have since been approved for the treatment of multiple cancer types. PD-1 is expressed by several subsets of activated CD8+ and CD4+ T cells and is highly expressed on exhausted CD8+ T cells that show diminished cytotoxic responses to antigens ([ 2 ][2], [ 3 ][3]). Moreover, the ligand for PD-1, PD-L1, is expressed by malignant cells as well as APCs, and high PD-L1 expression within the tumor can correlate with clinical efficacy ([ 1 ][1]). These data suggest that in contrast to CTLA-4 blockade, PD-1 blockade may act primarily on tumor-resident T cells. The reinvigoration of T cells in the TME, particularly exhausted T cells, was further supported by studies in mouse models of cancer and chronic viral infection, which demonstrated that PD-1 blockade could induce proliferation and effector properties in chronically stimulated T cells ([ 3 ][3]). However, it has been difficult to reconcile this singular paradigm of PD-1 action on tumor-resident T cells with observations that suggest a systemic immune response. For example, T cell proliferation and activation are prevalent within the tumor-draining lymph node (TDLN) and peripheral blood following PD-1 blockade in mouse tumor models ([ 4 ][4]). PD-L1 blockade within the TDLN promotes tumor rejection similar to that induced by systemic therapy, and the inhibition of T cell migration prior to PD-1 blockade abrogates tumor rejection, suggesting that the TDLN may act as a reservoir of PD-1 and PD-L1 blockade–responsive, tumor-reactive T cells ([ 4 ][4], [ 5 ][5]). Moreover, tumor regression following PD-1 blockade in mouse models is dependent on interactions between APC-derived B7 and the T cell costimulatory receptor CD28, which occur in the lymph node ([ 3 ][3]). In particular, recent studies highlighted the importance of PD-L1 expression on classical dendritic cells (cDCs), suggesting that PD-1 blockade may act at the level of cDC-dependent T cell priming and activation ([ 5 ][5], [ 6 ][6]). Further profiling of human T cell responses to PD-1 blockade in melanoma patients revealed increased T cell proliferation in the peripheral blood compared with the TME, suggesting that T cells may be activated peripherally and then recruited to the tumor ([ 7 ][7]). A systemic antitumor immune response to PD-1 blockade is further supported by synchronous regression of multiple metastatic lesions after treatment ([ 8 ][8]). Similar to the abscopal effect, which is characterized by distant responses to site-specific tumor radiotherapy ([ 9 ][9]), uniform patterns of response among individual metastases suggest that peripheral immune cells may play an important role in the clinical response to ICB ([ 8 ][8]). Genomic profiling has also demonstrated that T cell exhaustion is epigenetically fixed, suggesting that PD-1 blockade may be unable to rescue exhausted TILs ([ 3 ][3]). A productive immune response following ICB results in the clonal expansion of tumor-specific T cells, which can be tracked across different tissues and time points by profiling T cell receptor (TCR) sequences. TCR sequencing allows for preexisting T cell clones to be distinguished from newly activated T cells recruited from distant tissues. Early efforts to profile TCR dynamics in patients receiving anti-CTLA-4 therapy revealed a broadening of the peripheral T cell tumor-reactive TCR repertoire, supporting the idea that CTLA-4 blockade may lower the threshold of the strength of TCR signaling that is required for activation ([ 2 ][2]). Tracking of peripheral T cell clones using TCR sequencing before and after ICB demonstrated that melanoma patients with a clinical response to therapy have significantly more clonal expansion and T cell turnover following therapy compared with nonresponders ([ 10 ][10], [ 11 ][11]). However, whether peripherally activated T cells traffic to the tumor remained unclear. Profiling of phenotypic and clonal T cell dynamics in site-matched human basal and squamous cell carcinomas before and after PD-1 blockade revealed that CD8+ T cells with an exhausted phenotype are more clonally expanded relative to other TILs and also expressed surface markers characteristic of tumor-reactive T cells ([ 12 ][12]). Clonal expansion of exhausted T cells in response to therapy was predominantly derived from T cell clones that were not detected in the tumor prior to therapy, and this effect was specific to exhausted T cells. Notably, most preexisting intratumoral T cell clones could be found in the tumor after therapy but did not clonally expand, and preexisting exhausted T cell clones did not adopt a nonexhausted phenotype following treatment ([ 12 ][12]). This suggests that preexisting exhausted TILs may have limited reinvigoration potential and that clonal replacement of TILs from tumor-extrinsic sources is a major aspect of ICB responses. ![Figure][13] The cancer-immunity cycle of immune checkpoint blockade response Immune checkpoint blockade with anti–programmed cell death 1 (anti–PD-1) therapy blocks inhibitory signaling on T cells. The immune response to PD-1 blockade relies on invigoration of tumor-extrinsic T cells during T cell priming and activation within the tumor-draining lymph node (TDLN). Activated T cells traffic to the tumor where they kill cancer cells and release antigens that are presented to T cells by dendritic cells in the TDLN, linking tumor-resident and tumor-extrinsic immune responses. GRAPHIC: C. BICKEL/ SCIENCE Additional support for this role of tumor-extrinsic T cells comes from two studies tracking T cell clones in tumor, normal adjacent tissue, and peripheral blood. In lung, endometrial, colorectal, and renal cancers, expanded T cell clones within the tumor were commonly shared with adjacent normal tissue and peripheral blood ([ 13 ][14]). TIL clones with an exhausted phenotype were less likely to be detected in peripheral blood, suggesting that replenishment of TILs with peripheral T cells may provide a source of nonexhausted TILs. Furthermore, deep TCR profiling during neoadjuvant PD-1 blockade (prior to surgical resection) demonstrated that T cell clones that expanded in the peripheral blood following treatment were enriched within the tumor of responding patients, suggesting that expansion and subsequent infiltration of peripheral T cells may be associated with clinical response ([ 14 ][15]). Together, these studies support a model of tumor-extrinsic T cell responses to PD-1 blockade (see the figure). Interactions between PD-L1+ cDCs and T cells in the TDLN are a compelling target for PD-1 blockade ([ 5 ][5], [ 6 ][6]). After priming and activation, T cells can circulate in the peripheral blood and traffic to the primary tumor site, as well as metastases. Upon cancer cell killing, the release of tumor antigens and their subsequent presentation by migratory DCs in the TDLN provide a link between the tumor-extrinsic T cell response and the cancer-immunity cycle ([ 1 ][1]). It is important to note that the tumor-extrinsic T cell response to PD-1 blockade and the reactivation of preexisting TILs are not mutually exclusive and may represent complementary or synergistic mechanisms of response. Despite these advances, many questions remain. Although T cell clones that respond to PD-1 blockade can be found in the peripheral blood and TDLN, several possibilities regarding their precise site of activation are possible: clonal T cell priming and expansion in the TDLN and/or tertiary lymphoid sites followed by recruitment to the tumor; activation and expansion of a recently primed or unexpanded pool of progenitor T cells (such as stem cell memory or progenitor exhausted cells) within the TME and/or TDLN; or a combination of these possibilities, whereby activation of tumor-resident T cells accelerates recruitment of peripheral T cells to the TME through chemokine secretion or cDC activation. Given that most T cell proliferation in the peripheral blood occurs within 1 week of anti–PD-1 therapy and is largely diminished by 3 weeks ([ 7 ][7], [ 11 ][11]), what is the timing of clonal replacement? Does clonal T cell recruitment and expansion within the tumor follow the same kinetics? Chemical inhibition of T cell migration can abrogate tumor regression following ICB in some mouse models, but these results vary according to dosage and timing, indicating that such factors can influence therapeutic outcomes ([ 4 ][4], [ 15 ][16]). Another area of active investigation concerns how peripheral T cell dynamics are influenced by tumor-intrinsic factors, such as tumor site and mutational heterogeneity. Skin and lung cancers have been most extensively profiled and have high amounts of immune infiltration. Comparisons between metastatic sites suggested that tumors in more immunosuppressive tissue microenvironments (such as the liver) are the least responsive to PD-1 blockade, but how tumor location influences T cell dynamics during therapy remains unclear ([ 8 ][8]). Because clonal neoantigen burden is also associated with clinical response to ICB, and TILs reactive to clonal neoantigens are present prior to treatment ([ 1 ][1]), how do clonal antigens escape immune surveillance before ICB, and what is the relationship between tumor evolution and T cell dynamics? Distinguishing general immunological effects of PD-1 blockade from antitumor immune responses will require studies pairing TIL clonotypes to their target antigens to determine how T cell phenotypes and clonal dynamics are influenced by antigen specificity. Thus, it is possible that preexisting TILs represent a correlate, rather than a cause, of clinical responses in immune-infiltrated tumors. Namely, intratumoral immune infiltration may simply reflect TME properties such as mutational load, immunogenicity, and/or tumor site that promote continued surveillance by tumor-extrinsic T cells. Future investigations into the origins and mechanisms of response to ICB should help to identify prognostic factors underlying clinical efficacy and will facilitate the rational design of effective treatment combinations to improve responses. In particular, the combination of ICB with immune-modulating agents that amplify peripheral T cell recruitment, such as immunostimulatory agonist antibodies and cytokine-based immunotherapies, may expand the utility of ICB to a wider patient population. 1. [↵][17]1. D. S. Chen, 2. I. Mellman , Nature 541, 321 (2017). [OpenUrl][18][CrossRef][19][PubMed][20] 2. [↵][21]1. S. C. Wei, 2. C. R. Duffy, 3. J. P. Allison , Cancer Discov. 8, 1069 (2018). [OpenUrl][22][Abstract/FREE Full Text][23] 3. [↵][24]1. L. M. McLane, 2. M. S. Abdel-Hakeem, 3. E. J. Wherry , Annu. Rev. Immunol. 37, 457 (2019). [OpenUrl][25][CrossRef][26][PubMed][27] 4. [↵][28]1. M. H. Spitzer et al ., Cell 168, 487 (2017). [OpenUrl][29][CrossRef][30][PubMed][31] 5. [↵][32]1. F. Dammeijer et al ., Cancer Cell 38, 685 (2020). [OpenUrl][33] 6. [↵][34]1. S. A. Oh et al ., Nat. Can. 1, 681 (2020). [OpenUrl][35] 7. [↵][36]1. A. C. Huang et al ., Nat. Med. 25, 454 (2019). [OpenUrl][37][CrossRef][38][PubMed][39] 8. [↵][40]1. J. C. Osorio et al ., J. Clin. Oncol. 37, 3546 (2019). [OpenUrl][41][PubMed][27] 9. [↵][42]1. L. Hammerich et al ., Nat. Med. 25, 814 (2019). [OpenUrl][43][CrossRef][44][PubMed][27] 10. [↵][45]1. B. P. Fairfax et al ., Nat. Med. 26, 193 (2020). [OpenUrl][46][CrossRef][47] 11. [↵][48]1. S. Valpione et al ., Nat. Can. 1, 210 (2020). [OpenUrl][49] 12. [↵][50]1. K. E. Yost et al ., Nat. Med. 25, 1251 (2019). [OpenUrl][51][CrossRef][52][PubMed][53] 13. [↵][54]1. T. D. Wu et al ., Nature 579, 274 (2020). [OpenUrl][55][PubMed][27] 14. [↵][56]1. J. Zhang et al ., Clin. Cancer Res. 26, 1327 (2020). [OpenUrl][57][Abstract/FREE Full Text][58] 15. [↵][59]1. S. L. Topalian, 2. J. M. Taube, 3. D. M. Pardoll , Science 367, eaax0182 (2020). [OpenUrl][60][Abstract/FREE Full Text][61] Acknowledgments: A.T.S. is a scientific founder of Immunai. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio and an adviser to 10x Genomics, Arsenal Biosciences, and Spring Discovery. [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]: pending:yes [14]: #ref-13 [15]: #ref-14 [16]: #ref-15 [17]: #xref-ref-1-1 "View reference 1 in text" [18]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D541%26rft.spage%253D321%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnature21349%26rft_id%253Dinfo%253Apmid%252F28102259%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/external-ref?access_num=10.1038/nature21349&link_type=DOI [20]: /lookup/external-ref?access_num=28102259&link_type=MED&atom=%2Fsci%2F372%2F6538%2F130.atom [21]: #xref-ref-2-1 "View reference 2 in text" [22]: {openurl}?query=rft.jtitle%253DCancer%2BDiscov.%26rft_id%253Dinfo%253Adoi%252F10.1158%252F2159-8290.CD-18-0367%26rft_id%253Dinfo%253Apmid%252F30115704%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 [23]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NzoiY2FuZGlzYyI7czo1OiJyZXNpZCI7czo4OiI4LzkvMTA2OSI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM3Mi82NTM4LzEzMC5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [24]: #xref-ref-3-1 "View reference 3 in text" [25]: {openurl}?query=rft.jtitle%253DAnnu.%2BRev.%2BImmunol.%26rft.volume%253D37%26rft.spage%253D457%26rft_id%253Dinfo%253Adoi%252F10.1146%252Fannurev-immunol-041015-055318%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%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=10.1146/annurev-immunol-041015-055318&link_type=DOI [27]: /lookup/external-ref?access_num=http://www.n&link_type=MED&atom=%2Fsci%2F372%2F6538%2F130.atom [28]: #xref-ref-4-1 "View reference 4 in text" [29]: {openurl}?query=rft.jtitle%253DCell%26rft.volume%253D168%26rft.spage%253D487%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.cell.2016.12.022%26rft_id%253Dinfo%253Apmid%252F28111070%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 [30]: /lookup/external-ref?access_num=10.1016/j.cell.2016.12.022&link_type=DOI [31]: /lookup/external-ref?access_num=28111070&link_type=MED&atom=%2Fsci%2F372%2F6538%2F130.atom [32]: #xref-ref-5-1 "View reference 5 in text" [33]: {openurl}?query=rft.jtitle%253DCancer%2BCell%26rft.volume%253D38%26rft.spage%253D685%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 [34]: #xref-ref-6-1 "View reference 6 in text" [35]: {openurl}?query=rft.jtitle%253DNat.%2BCan.%26rft.volume%253D1%26rft.spage%253D681%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%253DNat.%2BMed.%26rft.volume%253D25%26rft.spage%253D454%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0357-y%26rft_id%253Dinfo%253Apmid%252F30804515%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/external-ref?access_num=10.1038/s41591-019-0357-y&link_type=DOI [39]: /lookup/external-ref?access_num=30804515&link_type=MED&atom=%2Fsci%2F372%2F6538%2F130.atom [40]: #xref-ref-8-1 "View reference 8 in text" [41]: {openurl}?query=rft.jtitle%253DJ.%2BClin.%2BOncol.%26rft.volume%253D37%26rft.spage%253D3546%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%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 [42]: #xref-ref-9-1 "View reference 9 in text" [43]: {openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D25%26rft.spage%253D814%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0410-x%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%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 [44]: /lookup/external-ref?access_num=10.1038/s41591-019-0410-x&link_type=DOI [45]: #xref-ref-10-1 "View reference 10 in text" [46]: {openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D26%26rft.spage%253D193%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0734-6%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 [47]: /lookup/external-ref?access_num=10.1038/s41591-019-0734-6&link_type=DOI [48]: #xref-ref-11-1 "View reference 11 in text" [49]: {openurl}?query=rft.jtitle%253DNat.%2BCan.%26rft.volume%253D1%26rft.spage%253D210%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 [50]: #xref-ref-12-1 "View reference 12 in text" [51]: {openurl}?query=rft.jtitle%253DNat.%2BMed.%26rft.volume%253D25%26rft.spage%253D1251%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41591-019-0522-3%26rft_id%253Dinfo%253Apmid%252F31359002%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/external-ref?access_num=10.1038/s41591-019-0522-3&link_type=DOI [53]: /lookup/external-ref?access_num=31359002&link_type=MED&atom=%2Fsci%2F372%2F6538%2F130.atom [54]: #xref-ref-13-1 "View reference 13 in text" [55]: {openurl}?query=rft.jtitle%253DNature%26rft.volume%253D579%26rft.spage%253D274%26rft_id%253Dinfo%253Apmid%252Fhttp%253A%252F%252Fwww.n%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 [56]: #xref-ref-14-1 "View reference 14 in text" [57]: {openurl}?query=rft.jtitle%253DClin.%2BCancer%2BRes.%26rft_id%253Dinfo%253Adoi%252F10.1158%252F1078-0432.CCR-19-2931%26rft_id%253Dinfo%253Apmid%252F31754049%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 [58]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNsaW5jYW5yZXMiO3M6NToicmVzaWQiO3M6OToiMjYvNi8xMzI3IjtzOjQ6ImF0b20iO3M6MjI6Ii9zY2kvMzcyLzY1MzgvMTMwLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ== [59]: #xref-ref-15-1 "View reference 15 in text" [60]: 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专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Kathryn E. Yost,Howard Y. Chang,Ansuman T. Satpathy. Recruiting T cells in cancer immunotherapy[J]. Science,2021.
APA	Kathryn E. Yost,Howard Y. Chang,&Ansuman T. Satpathy.(2021).Recruiting T cells in cancer immunotherapy.Science.
MLA	Kathryn E. Yost,et al."Recruiting T cells in cancer immunotherapy".Science (2021).