1. Foulkes, W. D., Smith, I. E. & Reis-Filho, J. S. Triple-negative breast cancer. N. Engl. J. Med. 363, 1938–1948. https://doi.org/10.
1056/NEJMra1001389 (2010).
Scientific Reports |
(2021) 11:21992 |
https://doi.org/10.1038/s41598-021-01455-4
Vol.:(0123456789)
www.nature.com/scientificreports/
2. Niikura, N. et al. Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype:
A multicenter retrospective analysis. Breast Cancer Res. Treat 147, 103–112. https://doi.org/10.1007/s10549-014-3090-8 (2014).
3. Lin, N. U. et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: High
incidence of central nervous system metastases. Cancer 113, 2638–2645. https://doi.org/10.1002/cncr.23930 (2008).
4. Beckers, R. K. et al. Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating
lymphocytes and improved outcome. Histopathology 69, 25–34. https://doi.org/10.1111/his.12904 (2016).
5. Shah, S. P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399.
https://doi.org/10.1038/nature10933 (2012).
6. Loi, S. et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer
trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy:
BIG 02–98. J. Clin. Oncol. 31, 860–867. https://doi.org/10.1200/jco.2011.41.0902 (2013).
7. Mittendorf, E. A. et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol. Res. 2, 361–370. https://doi.org/10.
1158/2326-6066.Cir-13-0127 (2014).
8. Wimberly, H. et al. PD-L1 expression correlates with tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy
in breast cancer. Cancer Immunol. Res. 3, 326–332. https://doi.org/10.1158/2326-6066.Cir-14-0133 (2015).
9. Schmid, P. et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121.
https://doi.org/10.1056/NEJMoa1809615 (2018).
10. Denkert, C. et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771
patients treated with neoadjuvant therapy. Lancet Oncol. 19, 40–50. https://doi.org/10.1016/s1470-2045(17)30904-x (2018).
11. Adams, S. et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized
adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32, 2959–2966. https://doi.org/10.1200/jco.2013.55.0491
(2014).
12. Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E. & Gianni, L. Triple-negative breast cancer: Challenges and opportunities
of a heterogeneous disease. Nat. Rev. Clin. Oncol. 13, 674–690. https://doi.org/10.1038/nrclinonc.2016.66 (2016).
13. Emens, L. A. et al. Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic
triple-negative breast cancer: A phase 1 study. JAMA Oncol. 5, 74–82. https://doi.org/10.1001/jamaoncol.2018.4224 (2019).
14. Eisenbarth, S. C. Dendritic cell subsets in T cell programming: Location dictates function. Nat. Rev. Immunol. 19, 89–103. https://
doi.org/10.1038/s41577-018-0088-1 (2019).
15. Guilliams, M. et al. Dendritic cells, monocytes and macrophages: A unified nomenclature based on ontogeny. Nat. Rev. Immunol.
14, 571–578. https://doi.org/10.1038/nri3712 (2014).
16. Shortman, K. & Heath, W. R. The CD8+ dendritic cell subset. Immunol. Rev. 234, 18–31. https://d
oi.o
rg/1 0.1 111/j.0 105-2 896.2 009.
00870.x (2010).
17. Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell
immunity. Cancer Cell 26, 638–652. https://doi.org/10.1016/j.ccell.2014.09.007 (2014).
18. Oba, T. et al. A critical role of CD40 and CD70 signaling in conventional type 1 dendritic cells in expansion and antitumor efficacy
of adoptively transferred tumor-specific T cells. J. Immunol. 205, 1867–1877. https://doi.org/10.4049/jimmunol.2000347 (2020).
19. Roberts, E. W. et al. Critical role for CD103(+)/CD141(+) dendritic cells bearing CCR7 for tumor antigen trafficking and priming
of T cell immunity in melanoma. Cancer Cell 30, 324–336. https://doi.org/10.1016/j.ccell.2016.06.003 (2016).
20. Hildner, K. et al. Batf3 deficiency reveals a critical role for CD8α+ dendritic cells in cytotoxic T cell immunity. Science 322,
1097–1100. https://doi.org/10.1126/science.1164206 (2008).
21. Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523,
231–235. https://doi.org/10.1038/nature14404 (2015).
22. Fuertes, M. B. et al. Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells. J.
Exp. Med. 208, 2005–2016. https://doi.org/10.1084/jem.20101159 (2011).
23. Spranger, S., Dai, D., Horton, B. & Gajewski, T. F. Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking
and adoptive T cell therapy. Cancer Cell 31, 711-723.e714. https://doi.org/10.1016/j.ccell.2017.04.003 (2017).
24. Sanchez-Paulete, A. R. et al. Cancer immunotherapy with immunomodulatory anti-CD137 and anti-PD-1 monoclonal antibodies
requires BATF3-dependent dendritic cells. Cancer Discov. 6, 71–79. https://doi.org/10.1158/2159-8290.cd-15-0510 (2016).
25. Salmon, H. et al. Expansion and activation of CD103(+) dendritic cell progenitors at the tumor site enhances tumor responses to
therapeutic PD-L1 and BRAF inhibition. Immunity 44, 924–938. https://doi.org/10.1016/j.immuni.2016.03.012 (2016).
26. Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25,
814–824. https://doi.org/10.1038/s41591-019-0410-x (2019).
27. Hegde, S. et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 37, 289–307.
https://doi.org/10.1016/j.ccell.2020.02.008 (2020).
28. Meyer, M. A. et al. Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune
surveillance. Nat. Commun. 9, 1250. https://doi.org/10.1038/s41467-018-03600-6 (2018).
29. Oba, T. et al. Overcoming primary and acquired resistance to anti-PD-L1 therapy by induction and activation of tumor-residing
cDC1s. Nat. Commun. 11, 5415. https://doi.org/10.1038/s41467-020-19192-z (2020).
30. Patel, A. et al. Multimodal intralesional therapy for reshaping the myeloid compartment of tumors resistant to anti-PD-L1 therapy
via IRF8 expression. J. Immunol. 207, 1298–1309. https://doi.org/10.4049/jimmunol.2100281 (2021).
31. Stewart, T. J., Liewehr, D. J., Steinberg, S. M., Greeneltch, K. M. & Abrams, S. I. Modulating the expression of IFN regulatory factor
8 alters the protumorigenic behavior of CD11b+Gr-1+ myeloid cells. J. Immunol. 183, 117–128. https://doi.org/10.4049/jimmu
nol.0804132 (2009).
32. Conley, F. K. Development of a metastatic brain tumor model in mice. Can. Res. 39, 1001–1007 (1979).
33. Zhang, L. et al. Blocking immunosuppressive neutrophils deters pY696-EZH2-driven brain metastases. Sci. Transl. Med. https://
doi.org/10.1126/scitranslmed.aaz5387 (2020).
34. Oba, T. et al. In situ delivery of iPSC-derived dendritic cells with local radiotherapy generates systemic antitumor immunity and
potentiates PD-L1 blockade in preclinical poorly immunogenic tumor models. J. Immunother. Cancer. https://doi.org/10.1136/
jitc-2021-002432 (2021).
35. Yamauchi, T. et al. T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors.
Nat. Commun. 12, 1402. https://doi.org/10.1038/s41467-021-21619-0 (2021).
36. Yamauchi, T. et al. CX3CR1-CD8+ T cells are critical in antitumor efficacy, but functionally suppressed in the tumor microenvironment. JCI insight 5, e133920. https://doi.org/10.1172/jci.insight.133920 (2020).
37. Saito, H., Okita, K., Chang, A. E. & Ito, F. Adoptive transfer of CD8+ T cells generated from induced pluripotent stem cells triggers regressions of large tumors along with immunological memory. Can. Res. 76, 3473–3483. https://doi.org/10.1158/0008-5472.
can-15-1742 (2016).
38. Wilson, E. H., Weninger, W. & Hunter, C. A. Trafficking of immune cells in the central nervous system. J. Clin. Investig. 120,
1368–1379. https://doi.org/10.1172/jci41911 (2010).
39. Berghoff, A. S. et al. Density of tumor-infiltrating lymphocytes correlates with extent of brain edema and overall survival time in
patients with brain metastases. Oncoimmunology 5, e1057388. https://doi.org/10.1080/2162402x.2015.1057388 (2016).
Scientific Reports |
Vol:.(1234567890)
(2021) 11:21992 |
https://doi.org/10.1038/s41598-021-01455-4
www.nature.com/scientificreports/
40. Lugade, A. A. et al. Local radiation therapy of B16 melanoma tumors increases the generation of tumor antigen-specific effector
cells that traffic to the tumor. J. Immunol. 174, 7516–7523. https://doi.org/10.4049/jimmunol.174.12.7516 (2005).
41. Lugade, A. A. et al. Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J. Immunol. 180, 3132–3139. https://doi.org/10.4049/jimmunol.180.5.3132 (2008).
42. Sharabi, A. B. et al. Stereotactic radiation therapy augments antigen-specific PD-1-mediated antitumor immune responses via
cross-presentation of tumor antigen. Cancer Immunol. Res. 3, 345–355. https://doi.org/10.1158/2326-6066.cir-14-0196 (2015).
43. Gupta, A. et al. Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J. Immunol. 189, 558–566.
https://doi.org/10.4049/jimmunol.1200563 (2012).
44. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: A beneficial liaison? Nat. Rev. Clin. Oncol.
14, 365–379. https://doi.org/10.1038/nrclinonc.2016.211 (2017).
45. Burnette, B. C. et al. The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Can. Res. 71, 2488–2496. https://doi.org/10.1158/0008-5472.Can-10-2820 (2011).
46. Reynders, K., Illidge, T., Siva, S., Chang, J. Y. & De Ruysscher, D. The abscopal effect of local radiotherapy: Using immunotherapy
to make a rare event clinically relevant. Cancer Treat Rev. 41, 503–510. https://doi.org/10.1016/j.ctrv.2015.03.011 (2015).
47. Luke, J. J. et al. Safety and clinical activity of pembrolizumab and multisite stereotactic body radiotherapy in patients with advanced
solid tumors. J. Clin. Oncol. 36, 1611–1618. https://doi.org/10.1200/jco.2017.76.2229 (2018).
48. Deng, L. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Investig. 124,
687–695. https://doi.org/10.1172/jci67313 (2014).
49. Demaria, S. & Formenti, S. C. Radiation as an immunological adjuvant: Current evidence on dose and fractionation. Front. Oncol.
2, 153. https://doi.org/10.3389/fonc.2012.00153 (2012).
50. Demaria, S. et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int. J. Radiat.
Oncol. Biol. Phys. 58, 862–870. https://doi.org/10.1016/j.ijrobp.2003.09.012 (2004).
51. Golden, E. B. et al. Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses
in patients with metastatic solid tumours: A proof-of-principle trial. Lancet Oncol. 16, 795–803. https://doi.org/10.1016/s1470-
2045(15)00054-6 (2015).
Acknowledgements
We acknowledge Drs. Tibor Keler and Henry Marsh in Celldex Therapeutics, Inc. for providing hFlt3L for this
study, BioRender.com for illustrations, and the Division of Laboratory Animal Resources, and Pathology Network
(Roswell Park) for technical assistance. This work was supported by Roswell Park Comprehensive Cancer Center
and National Cancer Institute Grant P30CA016056 involving the use of Roswell Park’s Flow and Image Cytometry
Shared Resource, Pathology Network, and the Onsite Supply Center, METAvivor and National Cancer Institute
Grant K08CA197966 and R01CA255240-01A1 [to F.I.] and R01CA172105 [to S.I.A.]. T.O. was supported by
Uehara Memorial Foundation.
Author contributions
T.Y. contributed development of methodology, acquisition of data, analysis and interpretation of data, writing,
and review of the manuscript. T.O. contributed development of methodology, acquisition of data, analysis and
interpretation of data, review, and revision of the manuscript. R.K. contributed acquisition of data, analysis and
interpretation of data, review, and revision of the manuscript. S.A. provided reagents (AT-3 tumors), and revised
the article. F.I. developed the concept and methodology, analyzed data, coordinated author activities, revised the
manuscript, and provided final approval of the version to be submitted.
Competing interests The authors declare no competing interests.
Additional information
Supplementary Information The online version contains supplementary material available at https://doi.org/
10.1038/s41598-021-01455-4.
Correspondence and requests for materials should be addressed to F.I.
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