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IL-20 antagonist suppresses PD-L1 expression and prolongs survival in pancreatic cancer models
  1. 1.

    Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Lee, J. W., Komar, C. A., Bengsch, F., Graham, K. & Beatty, G. L. Genetically engineered mouse models of pancreatic cancer: the KPC model (LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre), its variants, and their application in immuno-oncology drug discovery. Curr. Protoc. Pharmacol. 73, 14.39.11–14.39.20 (2016).

    Google Scholar 

  3. 3.

    Kruger, D., Yako, Y. Y., Devar, J., Lahoud, N. & Smith, M. Inflammatory cytokines and combined biomarker panels in pancreatic ductal adenocarcinoma: enhancing diagnostic accuracy. PLoS ONE 14, e0221169 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588.e10–602.e10 (2019).

    Google Scholar 

  5. 5.

    Hu, H., Jiao, F., Han, T. & Wang, L. W. Functional significance of macrophages in pancreatic cancer biology. Tumour Biol. 36, 9119–9126 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cassetta, L. & Kitamura, T. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front. Cell Dev. Biol. 6, 38 (2018).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Mace, T. A. et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67, 320–332 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    McClanahan, F. et al. Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Emicro-TCL1 CLL mouse model. Blood 126, 212–221 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nomi, T. et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 2151–2157 (2007).

    CAS  PubMed  Google Scholar 

  10. 10.

    O’Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, 1431–1438 (2019).

    PubMed Central  Google Scholar 

  11. 11.

    Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bolm, L. et al. The role of fibroblasts in pancreatic cancer: extracellular matrix versus paracrine factors. Transl. Oncol. 10, 578–588 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wei, L. et al. Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer. Cell Death Dis. 9, 1065 (2018).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Dewys, W. D. et al. Prognostic effect of weight loss prior tochemotherapy in cancer patients. Am. J. Med. 69, 491–497 (1980).

    CAS  PubMed  Google Scholar 

  15. 15.

    Fearon, K. C. The Sir David Cuthbertson Medal Lecture 1991. The mechanisms and treatment of weight loss in cancer. Proc. Nutr. Soc. 51, 251–265 (1992).

    CAS  PubMed  Google Scholar 

  16. 16.

    Bachmann, J. et al. Pancreatic cancer related cachexia: influence on metabolism and correlation to weight loss and pulmonary function. BMC Cancer 9, 255 (2009).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Gordon, J. N. et al. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54, 540–545 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tsoli, M. et al. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res. 72, 4372–4382 (2012).

    CAS  PubMed  Google Scholar 

  19. 19.

    Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

    ADS  CAS  PubMed  Google Scholar 

  20. 20.

    Arner, P., Bolinder, J., Engfeldt, P. & Ostman, J. The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation. Metabolism 30, 753–760 (1981).

    CAS  PubMed  Google Scholar 

  21. 21.

    Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Cahlin, C. et al. Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res. 60, 5488–5493 (2000).

    CAS  PubMed  Google Scholar 

  23. 23.

    Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004).

    CAS  PubMed  Google Scholar 

  24. 24.

    Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    CAS  PubMed  Google Scholar 

  25. 25.

    Dumoutier, L., Leemans, C., Lejeune, D., Kotenko, S. V. & Renauld, J. C. Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167, 3545–3549 (2001).

    CAS  PubMed  Google Scholar 

  26. 26.

    Kragstrup, T. W. et al. Increased interleukin (IL)-20 and IL-24 target osteoblasts and synovial monocytes in spondyloarthritis. Clin. Exp. Immunol. 189, 342–351 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Chiu, Y. S. et al. Anti-IL-20 monoclonal antibody inhibited tumor growth in hepatocellular carcinoma. Sci. Rep. 7, 17609 (2017).

    ADS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. J. Immunol. 188, 1981–1991 (2012).

    CAS  PubMed  Google Scholar 

  29. 29.

    Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody suppresses prostate cancer growth and bone osteolysis in murine models. PLoS ONE 10, e0139871 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hsu, Y. H., Wei, C. C., Shieh, D. B., Chan, C. H. & Chang, M. S. Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth. Mol. Cancer Res. 10, 1430–1439 (2012).

    CAS  PubMed  Google Scholar 

  31. 31.

    Sa, S. M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).

    CAS  PubMed  Google Scholar 

  32. 32.

    Hsu, Y. H. et al. Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 54, 2722–2733 (2006).

    CAS  PubMed  Google Scholar 

  33. 33.

    Chen, W. Y., Cheng, B. C., Jiang, M. J., Hsieh, M. Y. & Chang, M. S. IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 2090–2095 (2006).

    CAS  PubMed  Google Scholar 

  34. 34.

    Li, H. H. et al. Interleukin-20 induced cell death in renal epithelial cells and was associated with acute renal failure. Genes Immun. 9, 395–404 (2008).

    CAS  PubMed  Google Scholar 

  35. 35.

    Chen, W. Y. & Chang, M. S. IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. J. Immunol. 182, 5003–5012 (2009).

    CAS  PubMed  Google Scholar 

  36. 36.

    Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    CAS  PubMed  Google Scholar 

  37. 37.

    Wang, Y. et al. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med. Oncol. 32, 212 (2015).

    PubMed  Google Scholar 

  38. 38.

    Alsuliman, A. et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol. Cancer 14, 149 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Chiu, Y. S., Wei, C. C., Lin, Y. J., Hsu, Y. H. & Chang, M. S. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 60, 1003–1014 (2014).

    CAS  PubMed  Google Scholar 

  40. 40.

    Eppihimer, M. J. et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 9, 133–145 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Daley, D. et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J. Exp. Med. 214, 1711–1724 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Acharyya, S. et al. Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell 8, 421–432 (2005).

    CAS  PubMed  Google Scholar 

  44. 44.

    Legaspi, A., Jeevanandam, M., Starnes, H. F. Jr. & Brennan, M. F. Whole body lipid and energy metabolism in the cancer patient. Metabolism 36, 958–963 (1987).

    CAS  PubMed  Google Scholar 

  45. 45.

    Kir, S. et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100–104 (2014).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Agustsson, T. et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res. 67, 5531–5537 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Yang, X., Zhang, X., Heckmann, B. L., Lu, X. & Liu, J. Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-α (TNF-α)-induced lipolysis in adipocytes. J. Biol. Chem. 286, 40477–40485 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Tisdale, M. J. Mechanisms of cancer cachexia. Physiol. Rev. 89, 381–410 (2009).

    CAS  PubMed  Google Scholar 

  49. 49.

    Long, K. B., Collier, A. I. & Beatty, G. L. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance. Mol. Immunol. 110, 3–12 (2019).

    CAS  PubMed  Google Scholar 

  50. 50.

    Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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    Löhr, M. et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).

    PubMed  Google Scholar 

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    Anggorowati, N. et al. Histochemical and immunohistochemical study of α-SMA, collagen, and PCNA in epithelial ovarian neoplasm. Asian Pac. J. Cancer Prev. 18, 667–671 (2017).

    PubMed  PubMed Central  Google Scholar 

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    Das, S., Shapiro, B., Vucic, E. A., Vogt, S. & Bar-Sagi, D. Tumor cell-derived IL-1β promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 2080, 2019 (2020).

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Original Text (This is the original text for your reference.)

  1. 1.

    Guerra, C. et al. Pancreatitis-induced inflammation contributes to pancreatic cancer by inhibiting oncogene-induced senescence. Cancer Cell 19, 728–739 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Lee, J. W., Komar, C. A., Bengsch, F., Graham, K. & Beatty, G. L. Genetically engineered mouse models of pancreatic cancer: the KPC model (LSL-Kras(G12D/+);LSL-Trp53(R172H/+);Pdx-1-Cre), its variants, and their application in immuno-oncology drug discovery. Curr. Protoc. Pharmacol. 73, 14.39.11–14.39.20 (2016).

    Google Scholar 

  3. 3.

    Kruger, D., Yako, Y. Y., Devar, J., Lahoud, N. & Smith, M. Inflammatory cytokines and combined biomarker panels in pancreatic ductal adenocarcinoma: enhancing diagnostic accuracy. PLoS ONE 14, e0221169 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Cassetta, L. et al. Human tumor-associated macrophage and monocyte transcriptional landscapes reveal cancer-specific reprogramming, biomarkers, and therapeutic targets. Cancer Cell 35, 588.e10–602.e10 (2019).

    Google Scholar 

  5. 5.

    Hu, H., Jiao, F., Han, T. & Wang, L. W. Functional significance of macrophages in pancreatic cancer biology. Tumour Biol. 36, 9119–9126 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Cassetta, L. & Kitamura, T. Targeting tumor-associated macrophages as a potential strategy to enhance the response to immune checkpoint inhibitors. Front. Cell Dev. Biol. 6, 38 (2018).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Mace, T. A. et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut 67, 320–332 (2018).

    CAS  PubMed  Google Scholar 

  8. 8.

    McClanahan, F. et al. Mechanisms of PD-L1/PD-1-mediated CD8 T-cell dysfunction in the context of aging-related immune defects in the Emicro-TCL1 CLL mouse model. Blood 126, 212–221 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Nomi, T. et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 13, 2151–2157 (2007).

    CAS  PubMed  Google Scholar 

  10. 10.

    O’Reilly, E. M. et al. Durvalumab with or without tremelimumab for patients with metastatic pancreatic ductal adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol. 5, 1431–1438 (2019).

    PubMed Central  Google Scholar 

  11. 11.

    Ozdemir, B. C. et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Bolm, L. et al. The role of fibroblasts in pancreatic cancer: extracellular matrix versus paracrine factors. Transl. Oncol. 10, 578–588 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wei, L. et al. Cancer-associated fibroblasts promote progression and gemcitabine resistance via the SDF-1/SATB-1 pathway in pancreatic cancer. Cell Death Dis. 9, 1065 (2018).

    PubMed  PubMed Central  Google Scholar 

  14. 14.

    Dewys, W. D. et al. Prognostic effect of weight loss prior tochemotherapy in cancer patients. Am. J. Med. 69, 491–497 (1980).

    CAS  PubMed  Google Scholar 

  15. 15.

    Fearon, K. C. The Sir David Cuthbertson Medal Lecture 1991. The mechanisms and treatment of weight loss in cancer. Proc. Nutr. Soc. 51, 251–265 (1992).

    CAS  PubMed  Google Scholar 

  16. 16.

    Bachmann, J. et al. Pancreatic cancer related cachexia: influence on metabolism and correlation to weight loss and pulmonary function. BMC Cancer 9, 255 (2009).

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Gordon, J. N. et al. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut 54, 540–545 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Tsoli, M. et al. Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice. Cancer Res. 72, 4372–4382 (2012).

    CAS  PubMed  Google Scholar 

  19. 19.

    Das, S. K. et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 333, 233–238 (2011).

    ADS  CAS  PubMed  Google Scholar 

  20. 20.

    Arner, P., Bolinder, J., Engfeldt, P. & Ostman, J. The antilipolytic effect of insulin in human adipose tissue in obesity, diabetes mellitus, hyperinsulinemia, and starvation. Metabolism 30, 753–760 (1981).

    CAS  PubMed  Google Scholar 

  21. 21.

    Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014).

    CAS  PubMed  Google Scholar 

  22. 22.

    Cahlin, C. et al. Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res. 60, 5488–5493 (2000).

    CAS  PubMed  Google Scholar 

  23. 23.

    Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004).

    CAS  PubMed  Google Scholar 

  24. 24.

    Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    CAS  PubMed  Google Scholar 

  25. 25.

    Dumoutier, L., Leemans, C., Lejeune, D., Kotenko, S. V. & Renauld, J. C. Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167, 3545–3549 (2001).

    CAS  PubMed  Google Scholar 

  26. 26.

    Kragstrup, T. W. et al. Increased interleukin (IL)-20 and IL-24 target osteoblasts and synovial monocytes in spondyloarthritis. Clin. Exp. Immunol. 189, 342–351 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Chiu, Y. S. et al. Anti-IL-20 monoclonal antibody inhibited tumor growth in hepatocellular carcinoma. Sci. Rep. 7, 17609 (2017).

    ADS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. J. Immunol. 188, 1981–1991 (2012).

    CAS  PubMed  Google Scholar 

  29. 29.

    Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody suppresses prostate cancer growth and bone osteolysis in murine models. PLoS ONE 10, e0139871 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. 30.

    Hsu, Y. H., Wei, C. C., Shieh, D. B., Chan, C. H. & Chang, M. S. Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth. Mol. Cancer Res. 10, 1430–1439 (2012).

    CAS  PubMed  Google Scholar 

  31. 31.

    Sa, S. M. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J. Immunol. 178, 2229–2240 (2007).

    CAS  PubMed  Google Scholar 

  32. 32.

    Hsu, Y. H. et al. Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 54, 2722–2733 (2006).

    CAS  PubMed  Google Scholar 

  33. 33.

    Chen, W. Y., Cheng, B. C., Jiang, M. J., Hsieh, M. Y. & Chang, M. S. IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 26, 2090–2095 (2006).

    CAS  PubMed  Google Scholar 

  34. 34.

    Li, H. H. et al. Interleukin-20 induced cell death in renal epithelial cells and was associated with acute renal failure. Genes Immun. 9, 395–404 (2008).

    CAS  PubMed  Google Scholar 

  35. 35.

    Chen, W. Y. & Chang, M. S. IL-20 is regulated by hypoxia-inducible factor and up-regulated after experimental ischemic stroke. J. Immunol. 182, 5003–5012 (2009).

    CAS  PubMed  Google Scholar 

  36. 36.

    Hingorani, S. R. et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005).

    CAS  PubMed  Google Scholar 

  37. 37.

    Wang, Y. et al. PD-L1 induces epithelial-to-mesenchymal transition via activating SREBP-1c in renal cell carcinoma. Med. Oncol. 32, 212 (2015).

    PubMed  Google Scholar 

  38. 38.

    Alsuliman, A. et al. Bidirectional crosstalk between PD-L1 expression and epithelial to mesenchymal transition: significance in claudin-low breast cancer cells. Mol. Cancer 14, 149 (2015).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Chiu, Y. S., Wei, C. C., Lin, Y. J., Hsu, Y. H. & Chang, M. S. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 60, 1003–1014 (2014).

    CAS  PubMed  Google Scholar 

  40. 40.

    Eppihimer, M. J. et al. Expression and regulation of the PD-L1 immunoinhibitory molecule on microvascular endothelial cells. Microcirculation 9, 133–145 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Daley, D. et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J. Exp. Med. 214, 1711–1724 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Acharyya, S. et al. Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia. Cancer Cell 8, 421–432 (2005).

    CAS  PubMed  Google Scholar 

  44. 44.

    Legaspi, A., Jeevanandam, M., Starnes, H. F. Jr. & Brennan, M. F. Whole body lipid and energy metabolism in the cancer patient. Metabolism 36, 958–963 (1987).

    CAS  PubMed  Google Scholar 

  45. 45.

    Kir, S. et al. Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100–104 (2014).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Agustsson, T. et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res. 67, 5531–5537 (2007).

    CAS  PubMed  Google Scholar 

  47. 47.

    Yang, X., Zhang, X., Heckmann, B. L., Lu, X. & Liu, J. Relative contribution of adipose triglyceride lipase and hormone-sensitive lipase to tumor necrosis factor-α (TNF-α)-induced lipolysis in adipocytes. J. Biol. Chem. 286, 40477–40485 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Tisdale, M. J. Mechanisms of cancer cachexia. Physiol. Rev. 89, 381–410 (2009).

    CAS  PubMed  Google Scholar 

  49. 49.

    Long, K. B., Collier, A. I. & Beatty, G. L. Macrophages: key orchestrators of a tumor microenvironment defined by therapeutic resistance. Mol. Immunol. 110, 3–12 (2019).

    CAS  PubMed  Google Scholar 

  50. 50.

    Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6C(low) F4/80(+) extratumoral macrophages. Gastroenterology 149, 201–210 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Löhr, M. et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).

    PubMed  Google Scholar 

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