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  • Perspective
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Cancer stem cell–immune cell crosstalk in tumour progression

Nature Reviews Cancer volume 21, pages 526–536 (2021)Cite this article

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Abstract

Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC–immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.

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Fig. 1: A unique set of mediators informs the communication between cancer stem cells and innate immune cell populations.
Fig. 2: CSCs interfere with T cell activity directly or through immunosuppressive myeloid cells.

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References

  1. Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Saygin, C., Matei, D., Majeti, R., Reizes, O. & Lathia, J. D. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell 24, 25–40 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Clara, J. A., Monge, C., Yang, Y. & Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update. Nat. Rev. Clin. Oncol. 17, 204–232 (2020).

    Article  PubMed  Google Scholar 

  4. Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & Lopez-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 (2018).

    Article  PubMed  CAS  Google Scholar 

  5. Hinshaw, D. C. & Shevde, L. A. The tumor microenvironment innately modulates cancer progression. Cancer Res. 79, 4557–4566 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Miranda, A. et al. Cancer stemness, intratumoral heterogeneity, and immune response across cancers. Proc. Natl Acad. Sci. USA 116, 9020–9029 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016).

    Article  CAS  PubMed  Google Scholar 

  8. Davies, L. C., Jenkins, S. J., Allen, J. E. & Taylor, P. R. Tissue-resident macrophages. Nat. Immunol. 14, 986–995 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Raggi, C. et al. Cholangiocarcinoma stem-like subset shapes tumor-initiating niche by educating associated macrophages. J. Hepatol. 66, 102–115 (2017).

    Article  CAS  PubMed  Google Scholar 

  11. Hide, T. et al. Oligodendrocyte progenitor cells and macrophages/microglia produce glioma stem cell niches at the tumor border. EBioMedicine 30, 94–104 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Huang, Y. K. et al. Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry. Nat. Commun. 10, 3928 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Bowman, R. L. et al. Macrophage ontogeny underlies differences in tumor-specific education in brain malignancies. Cell Rep. 17, 2445–2459 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588–602 e510 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hashimoto, D. et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity 38, 792–804 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Ginhoux, F. & Guilliams, M. Tissue-resident macrophage ontogeny and homeostasis. Immunity 44, 439–449 (2016).

    Article  CAS  PubMed  Google Scholar 

  17. Laviron, M. & Boissonnas, A. Ontogeny of tumor-associated macrophages. Front. Immunol. 10, 1799 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Tao, W. et al. Dual role of WISP1 in maintaining glioma stem cells and tumor-supportive macrophages in glioblastoma. Nat. Commun. 11, 3015 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhou, W. et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat. Cell Biol. 17, 170–182 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guo, X. et al. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 31, 247–259 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Wu, A. et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 12, 1113–1125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yi, L. et al. Glioma-initiating cells: a predominant role in microglia/macrophages tropism to glioma. J. Neuroimmunol. 232, 75–82 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Guo, X., Pan, Y. & Gutmann, D. H. Genetic and genomic alterations differentially dictate low-grade glioma growth through cancer stem cell-specific chemokine recruitment of T cells and microglia. Neuro Oncol. 21, 1250–1262 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Jinushi, M. et al. Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells. Proc. Natl Acad. Sci. USA 108, 12425–12430 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fan, Q. M. et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 352, 160–168 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Lu, H. et al. A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat. Cell Biol. 16, 1105–1117 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shi, Y. et al. Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat. Commun. 8, 15080 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wan, S. et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology 147, 1393–1404 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Zhang, B. et al. Macrophage-expressed CD51 promotes cancer stem cell properties via the TGF-beta1/smad2/3 axis in pancreatic cancer. Cancer Lett. 459, 204–215 (2019).

    Article  CAS  PubMed  Google Scholar 

  31. Su, W. et al. The Polycomb repressor complex 1 drives double-negative prostate cancer metastasis by coordinating stemness and immune suppression. Cancer Cell 36, 139–155 e110 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Cannarile, M. A. et al. Colony-stimulating factor 1 receptor (CSF1R) inhibitors in cancer therapy. J. Immunother. Cancer 5, 53 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Theocharides, A. P. et al. Disruption of SIRPalpha signaling in macrophages eliminates human acute myeloid leukemia stem cells in xenografts. J. Exp. Med. 209, 1883–1899 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee, T. K. et al. Blockade of CD47-mediated cathepsin S/protease-activated receptor 2 signaling provides a therapeutic target for hepatocellular carcinoma. Hepatology 60, 179–191 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Cioffi, M. et al. Inhibition of CD47 effectively targets pancreatic cancer stem cells via dual mechanisms. Clin. Cancer Res. 21, 2325–2337 (2015).

    Article  CAS  PubMed  Google Scholar 

  36. Liu, L. et al. Anti-CD47 antibody as a targeted therapeutic agent for human lung cancer and cancer stem cells. Front. Immunol. 8, 404 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hutter, G. et al. Microglia are effector cells of CD47-SIRPalpha antiphagocytic axis disruption against glioblastoma. Proc. Natl Acad. Sci. USA 116, 997–1006 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sikic, B. I. et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 37, 946–953 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kenkel, J. A. et al. An immunosuppressive dendritic cell subset accumulates at secondary sites and promotes metastasis in pancreatic cancer. Cancer Res. 77, 4158–4170 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Barilla, R. M. et al. Specialized dendritic cells induce tumor-promoting IL-10+IL-17+ FoxP3neg regulatory CD4+ T cells in pancreatic carcinoma. Nat. Commun. 10, 1424 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Grange, C. et al. Role of HLA-G and extracellular vesicles in renal cancer stem cell-induced inhibition of dendritic cell differentiation. BMC Cancer 15, 1009 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Liang, S. et al. Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6–STAT3 signaling pathway. Proc. Natl Acad. Sci. USA 105, 8357–8362 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hsu, Y. L. et al. Interaction between tumor-associated dendritic cells and colon cancer cells contributes to tumor progression via CXCL1. Int. J. Mol. Sci. https://doi.org/10.3390/ijms19082427 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wang, D., Sun, H., Wei, J., Cen, B. & DuBois, R. N. CXCL1 is critical for premetastatic niche formation and metastasis in colorectal cancer. Cancer Res. 77, 3655–3665 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lee, C. G. et al. A rare fraction of drug-resistant follicular lymphoma cancer stem cells interacts with follicular dendritic cells to maintain tumourigenic potential. Br. J. Haematol. 158, 79–90 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Pellegatta, S. et al. Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res. 66, 10247–10252 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Ning, N. et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 72, 1853–1864 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lechner, M. G. et al. Immunogenicity of murine solid tumor models as a defining feature of in vivo behavior and response to immunotherapy. J. Immunother. 36, 477–489 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Veglia, F., Sanseviero, E. & Gabrilovich, D. I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. https://doi.org/10.1038/s41577-020-00490-y (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Ouzounova, M. et al. Monocytic and granulocytic myeloid derived suppressor cells differentially regulate spatiotemporal tumour plasticity during metastatic cascade. Nat. Commun. 8, 14979 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhou, J., Nefedova, Y., Lei, A. & Gabrilovich, D. Neutrophils and PMN-MDSC: their biological role and interaction with stromal cells. Semin. Immunol. 35, 19–28 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. Cui, T. X. et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity 39, 611–621 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Panni, R. Z. et al. Tumor-induced STAT3 activation in monocytic myeloid-derived suppressor cells enhances stemness and mesenchymal properties in human pancreatic cancer. Cancer Immunol. Immunother. 63, 513–528 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Peng, D. et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 76, 3156–3165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Otvos, B. et al. Cancer stem cell-secreted macrophage migration inhibitory factor stimulates myeloid derived suppressor cell function and facilitates glioblastoma immune evasion. Stem Cell 34, 2026–2039 (2016).

    Article  CAS  Google Scholar 

  56. Alban, T. J. et al. Glioblastoma myeloid-derived suppressor cell subsets express differential macrophage migration inhibitory factor receptor profiles that can be targeted to reduce immune suppression. Front. Immunol. 11, 1191 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, G. et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov. 6, 80–95 (2016).

    Article  PubMed  CAS  Google Scholar 

  58. Shidal, C., Singh, N. P., Nagarkatti, P. & Nagarkatti, M. MicroRNA-92 expression in CD133+ melanoma stem cells regulates immunosuppression in the tumor microenvironment via integrin-dependent activation of TGFbeta. Cancer Res. 79, 3622–3635 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Kuroda, H. et al. Prostaglandin E2 produced by myeloid-derived suppressive cells induces cancer stem cells in uterine cervical cancer. Oncotarget 9, 36317–36330 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ai, L. et al. Myeloid-derived suppressor cells endow stem-like qualities to multiple myeloma cells by inducing piRNA-823 expression and DNMT3B activation. Mol. Cancer 18, 88 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wang, Y. et al. Granulocytic myeloid-derived suppressor cells promote the stemness of colorectal cancer cells through exosomal S100A9. Adv. Sci. 6, 1901278 (2019).

    Article  CAS  Google Scholar 

  62. Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhou, S. L. et al. A positive feedback loop between cancer stem-like cells and tumor-associated neutrophils controls hepatocellular carcinoma progression. Hepatology 70, 1214–1230 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. Di Tomaso, T. et al. Immunobiological characterization of cancer stem cells isolated from glioblastoma patients. Clin. Cancer Res. 16, 800–813 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Volonte, A. et al. Cancer-initiating cells from colorectal cancer patients escape from T cell-mediated immunosurveillance in vitro through membrane-bound IL-4. J. Immunol. 192, 523–532 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Morrison, B. J., Steel, J. C. & Morris, J. C. Reduction of MHC-I expression limits T-lymphocyte-mediated killing of cancer-initiating cells. BMC Cancer 18, 469 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Schatton, T. et al. Modulation of T-cell activation by malignant melanoma initiating cells. Cancer Res. 70, 697–708 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Paczulla, A. M. et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion. Nature 572, 254–259 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Wu, A. et al. Expression of MHC I and NK ligands on human CD133+ glioma cells: possible targets of immunotherapy. J. Neurooncol. 83, 121–131 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Tallerico, R. et al. Human NK cells selective targeting of colon cancer-initiating cells: a role for natural cytotoxicity receptors and MHC class I molecules. J. Immunol. 190, 2381–2390 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Beier, C. P. et al. The cancer stem cell subtype determines immune infiltration of glioblastoma. Stem Cell Dev. 21, 2753–2761 (2012).

    Article  CAS  Google Scholar 

  72. Sharonov, G. V., Serebrovskaya, E. O., Yuzhakova, D. V., Britanova, O. V. & Chudakov, D. M. B cells, plasma cells and antibody repertoires in the tumour microenvironment. Nat. Rev. Immunol. 20, 294–307 (2020).

    Article  CAS  PubMed  Google Scholar 

  73. Bruchard, M. & Ghiringhelli, F. Deciphering the roles of innate lymphoid cells in cancer. Front. Immunol. 10, 656 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. You, Y. et al. Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells. Clin. Exp. Immunol. 191, 60–73 (2018).

    Article  CAS  PubMed  Google Scholar 

  76. Xu, Y. et al. Sox2 communicates with Tregs through CCL1 to promote the stemness property of breast cancer cells. Stem Cell 35, 2351–2365 (2017).

    Article  CAS  Google Scholar 

  77. Chang, A. L. et al. CCL2 produced by the glioma microenvironment is essential for the recruitment of regulatory T cells and myeloid-derived suppressor cells. Cancer Res. 76, 5671–5682 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ban, Y. et al. Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity. Cancer Res. 77, 2857–2868 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Eruslanov, E. et al. Expansion of CCR8+ inflammatory myeloid cells in cancer patients with urothelial and renal carcinomas. Clin. Cancer Res. 19, 1670–1680 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

    Article  CAS  PubMed  Google Scholar 

  81. Wainwright, D. A. et al. IDO expression in brain tumors increases the recruitment of regulatory T cells and negatively impacts survival. Clin. Cancer Res. 18, 6110–6121 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nakano, M. et al. Dedifferentiation process driven by TGF-beta signaling enhances stem cell properties in human colorectal cancer. Oncogene 38, 780–793 (2019).

    Article  CAS  PubMed  Google Scholar 

  83. Ozawa, Y. et al. Indoleamine 2,3-dioxygenase 1 is highly expressed in glioma stem cells. Biochem. Biophys. Res. Commun. 524, 723–729 (2020).

    Article  CAS  PubMed  Google Scholar 

  84. Stapelberg, M. et al. Indoleamine-2,3-dioxygenase elevated in tumor-initiating cells is suppressed by mitocans. Free Radic. Biol. Med. 67, 41–50 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Sharma, M. D. et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113, 6102–6111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gagliani, N. et al. Th17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature 523, 221–225 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Martin, F., Apetoh, L. & Ghiringhelli, F. Controversies on the role of Th17 in cancer: a TGF-beta-dependent immunosuppressive activity? Trends Mol. Med. 18, 742–749 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Yang, S. et al. Foxp3+IL-17+ T cells promote development of cancer-initiating cells in colorectal cancer. J. Leukoc. Biol. 89, 85–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Zhang, Y. et al. Immune cell production of interleukin 17 induces stem cell features of pancreatic intraepithelial neoplasia cells. Gastroenterology 155, 210–223 e213 (2018).

    Article  CAS  PubMed  Google Scholar 

  90. Wang, R. et al. Th17 cell-derived IL-17A promoted tumor progression via STAT3/NF-kappaB/Notch1 signaling in non-small cell lung cancer. Oncoimmunology 7, e1461303 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  91. He, W. et al. IL22RA1/STAT3 signaling promotes stemness and tumorigenicity in pancreatic cancer. Cancer Res. 78, 3293–3305 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Jiang, R. et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13, 59 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell 177, 1172–1186 e1114 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Wu, Y. et al. Increased PD-L1 expression in breast and colon cancer stem cells. Clin. Exp. Pharmacol. Physiol. 44, 602–604 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Hsu, J. M. et al. STT3-dependent PD-L1 accumulation on cancer stem cells promotes immune evasion. Nat. Commun. 9, 1908 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Zhi, Y. et al. B7H1 expression and epithelial-to-mesenchymal transition phenotypes on colorectal cancer stem-like cells. PLoS ONE 10, e0135528 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Lee, Y. et al. CD44+ cells in head and neck squamous cell carcinoma suppress T-cell-mediated immunity by selective constitutive and inducible expression of PD-L1. Clin. Cancer Res. 22, 3571–3581 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yao, Y. et al. B7-H4(B7x)-mediated cross-talk between glioma-initiating cells and macrophages via the IL6/JAK/STAT3 pathway lead to poor prognosis in glioma patients. Clin. Cancer Res. 22, 2778–2790 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wei, J. et al. Glioblastoma cancer-initiating cells inhibit T-cell proliferation and effector responses by the signal transducers and activators of transcription 3 pathway. Mol. Cancer Ther. 9, 67–78 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Domenis, R. et al. Systemic T cells immunosuppression of glioma stem cell-derived exosomes is mediated by monocytic myeloid-derived suppressor cells. PLoS ONE 12, e0169932 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Gabrusiewicz, K. et al. Glioblastoma stem cell-derived exosomes induce M2 macrophages and PD-L1 expression on human monocytes. Oncoimmunology 7, e1412909 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Mirzaei, R. et al. Brain tumor-initiating cells export tenascin-C associated with exosomes to suppress T cell activity. Oncoimmunology 7, e1478647 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Jachetti, E. et al. Tenascin-C protects cancer stem-like cells from immune surveillance by arresting T-cell activation. Cancer Res. 75, 2095–2108 (2015).

    Article  CAS  PubMed  Google Scholar 

  104. Stein, R. G. et al. Cognate nonlytic interactions between CD8+ T cells and breast cancer cells induce cancer stem cell-like properties. Cancer Res. 79, 1507–1519 (2019).

    Article  CAS  PubMed  Google Scholar 

  105. Wang, D. et al. CRISPR screening of CAR T cells and cancer stem cells reveals critical dependencies for cell-based therapies. Cancer Discov. https://doi.org/10.1158/2159-8290.CD-20-1243 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Clocchiatti, A., Cora, E., Zhang, Y. & Dotto, G. P. Sexual dimorphism in cancer. Nat. Rev. Cancer 16, 330–339 (2016).

    Article  CAS  PubMed  Google Scholar 

  107. Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat. Rev. Immunol. 16, 626–638 (2016).

    Article  CAS  PubMed  Google Scholar 

  108. Sun, T. et al. Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males. J. Clin. Invest. 124, 4123–4133 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bayik, D. et al. Myeloid-derived suppressor cell subsets drive glioblastoma growth in a sex-specific manner. Cancer Discov. 10, 1210–1225 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Fillmore, C. M. et al. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc. Natl Acad. Sci. USA 107, 21737–21742 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Sun, Y. et al. Estrogen promotes stemness and invasiveness of ER-positive breast cancer cells through Gli1 activation. Mol. Cancer 13, 137 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Svoronos, N. et al. Tumor cell-independent estrogen signaling drives disease progression through mobilization of myeloid-derived suppressor cells. Cancer Discov. 7, 72–85 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Generali, D. et al. Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin. Cancer Res. 15, 1046–1051 (2009).

    Article  CAS  PubMed  Google Scholar 

  114. Sarmiento-Castro, A. et al. Increased expression of interleukin-1 receptor characterizes anti-estrogen-resistant ALDH+ breast cancer stem cells. Stem Cell Rep. 15, 307–316 (2020).

    Article  CAS  Google Scholar 

  115. White, M. C. et al. Age and cancer risk: a potentially modifiable relationship. Am. J. Prev. Med. 46, S7–15 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Ge, Y. et al. Stem cell lineage infidelity drives wound repair and cancer. Cell 169, 636–650 e614 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kalamakis, G. et al. Quiescence modulates stem cell maintenance and regenerative capacity in the aging brain. Cell 176, 1407–1419 e1414 (2019).

    Article  CAS  PubMed  Google Scholar 

  118. Agudo, J. et al. Quiescent tissue stem cells evade immune surveillance. Immunity 48, 271–285 e275 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bocci, F. et al. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc. Natl Acad. Sci. USA 116, 148–157 (2019).

    Article  CAS  PubMed  Google Scholar 

  120. Kaler, P., Godasi, B. N., Augenlicht, L. & Klampfer, L. The NF-kappaB/AKT-dependent induction of Wnt signaling in colon cancer cells by macrophages and IL-1beta. Cancer Microenviron. 2, 69–80 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Marquez, E. J. et al. Sexual-dimorphism in human immune system aging. Nat. Commun. 11, 751 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Li, Y., Wang, L., Pappan, L., Galliher-Beckley, A. & Shi, J. IL-1beta promotes stemness and invasiveness of colon cancer cells through Zeb1 activation. Mol. Cancer 11, 87 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Nomura, A. et al. NFkappaB-mediated invasiveness in CD133+ pancreatic TICs is regulated by autocrine and paracrine activation of IL1 signaling. Mol. Cancer Res. 16, 162–172 (2018).

    Article  CAS  PubMed  Google Scholar 

  125. Lauby-Secretan, B. et al. Body fatness and cancer–viewpoint of the IARC Working Group. N. Engl. J. Med. 375, 794–798 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Duan, Y. et al. Inflammatory links between high fat diets and diseases. Front. Immunol. 9, 2649 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Li, X. F. et al. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology 66, 1934–1951 (2017).

    Article  CAS  PubMed  Google Scholar 

  129. Beyaz, S. et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Yoshimoto, S. et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499, 97–101 (2013).

    Article  CAS  PubMed  Google Scholar 

  131. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  132. Luo, Y. et al. Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche. Cell Metab. 22, 886–894 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 e112 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Mager, L. F. et al. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science 369, 1481–1489 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  137. Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Routy, B. et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91–97 (2018).

    Article  CAS  PubMed  Google Scholar 

  139. Riquelme, E. et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178, 795–806 e712 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Lathia, J. D., Mack, S. C., Mulkearns-Hubert, E. E., Valentim, C. L. & Rich, J. N. Cancer stem cells in glioblastoma. Genes Dev. 29, 1203–1217 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Yamashina, T. et al. Cancer stem-like cells derived from chemoresistant tumors have a unique capacity to prime tumorigenic myeloid cells. Cancer Res. 74, 2698–2709 (2014).

    Article  CAS  PubMed  Google Scholar 

  142. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Mitchem, J. B. et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 73, 1128–1141 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Raghavan, S., Mehta, P., Xie, Y., Lei, Y. L. & Mehta, G. Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments. J. Immunother. Cancer 7, 190 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Zou, S. et al. Targeting STAT3 in cancer immunotherapy. Mol. Cancer 19, 145 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ciardiello, D., Elez, E., Tabernero, J. & Seoane, J. Clinical development of therapies targeting TGFbeta: current knowledge and future perspectives. Ann. Oncol. 31, 1336–1349 (2020).

    Article  CAS  PubMed  Google Scholar 

  147. Laplane, L. & Solary, E. Towards a classification of stem cells. eLife https://doi.org/10.7554/eLife.46563 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Naik, S., Larsen, S. B., Cowley, C. J. & Fuchs, E. Two to Tango: dialog between immunity and stem cells in health and disease. Cell 175, 908–920 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Sehgal, A. et al. The role of CSF1R-dependent macrophages in control of the intestinal stem-cell niche. Nat. Commun. 9, 1272 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  150. Chow, A. et al. Bone marrow CD169+ macrophages promote the retention of hematopoietic stem and progenitor cells in the mesenchymal stem cell niche. J. Exp. Med. 208, 261–271 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gyorki, D. E., Asselin-Labat, M. L., van Rooijen, N., Lindeman, G. J. & Visvader, J. E. Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 11, R62 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Van Nguyen, A. & Pollard, J. W. Colony stimulating factor-1 is required to recruit macrophages into the mammary gland to facilitate mammary ductal outgrowth. Dev. Biol. 247, 11–25 (2002).

    Article  PubMed  CAS  Google Scholar 

  153. Chakrabarti, R. et al. Notch ligand Dll1 mediates cross-talk between mammary stem cells and the macrophageal niche. Science https://doi.org/10.1126/science.aan4153 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Chen, C. C. et al. Organ-level quorum sensing directs regeneration in hair stem cell populations. Cell 161, 277–290 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Fujisaki, J. et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474, 216–219 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129 e1111 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Hirata, Y. et al. CD150high bone marrow Tregs maintain hematopoietic stem cell quiescence and immune privilege via adenosine. Cell Stem Cell 22, 445–453 e445 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320 e1322 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Bellomo, C., Caja, L. & Moustakas, A. Transforming growth factor beta as regulator of cancer stemness and metastasis. Br. J. Cancer 115, 761–769 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank E. Mulkearns-Hubert for editorial assistance. Work in the Lathia laboratory is supported by the Cleveland Clinic, Case Comprehensive Cancer Center, the American Brain Tumor Association, the US National Brain Tumor Society and the NIH (R01 NS109742, R01 NS117104 and P01 CA245705 (J.L.) and F32CA243314 and K99CA248611 (D.B.)).

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  1. Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Defne Bayik & Justin D. Lathia

  2. Case Comprehensive Cancer Center, Cleveland, OH, USA

    Defne Bayik & Justin D. Lathia

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  1. Defne Bayik
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Both authors researched data for the article, substantially contributed to discussion of the content, and wrote, reviewed and edited the manuscript before submission.

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Bayik, D., Lathia, J.D. Cancer stem cell–immune cell crosstalk in tumour progression. Nat Rev Cancer 21, 526–536 (2021). https://doi.org/10.1038/s41568-021-00366-w

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