TY - JOUR
T1 - Complement as prognostic biomarker and potential therapeutic target in renal cell carcinoma
AU - Reese, Britney
AU - Silwal, Ashok
AU - Daugherity, Elizabeth
AU - Daugherity, Michael
AU - Arabi, Mahshid
AU - Daly, Pierce
AU - Paterson, Yvonne
AU - Woolford, Layton
AU - Christie, Alana
AU - Elias, Roy
AU - Brugarolas, James
AU - Wang, Tao
AU - Karbowniczek, Magdalena
AU - Markiewski, Maciej M.
N1 - Publisher Copyright:
Copyright 2020 by The American Association of Immunologists, Inc.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.
AB - Preclinical studies demonstrated that complement promotes tumor growth. Therefore, we sought to determine the best target for complement-based therapy among common human malignancies. High expression of 11 complement genes was linked to unfavorable prognosis in renal cell carcinoma. Complement protein expression or deposition was observed mainly in stroma, leukocytes, and tumor vasculature, corresponding to a role of complement in regulating the tumor microenvironment. Complement abundance in tumors correlated with a high nuclear grade. Complement genes clustered within an aggressive inflammatory subtype of renal cancer characterized by poor prognosis, markers of T cell dysfunction, and alternatively activated macrophages. Plasma levels of complement proteins correlated with response to immune checkpoint inhibitors. Corroborating human data, complement deficiencies and blockade reduced tumor growth by enhancing antitumor immunity and seemingly reducing angiogenesis in a mouse model of kidney cancer resistant to PD-1 blockade. Overall, this study implicates complement in the immune landscape of renal cell carcinoma, and notwithstanding cohort size and preclinical model limitations, the data suggest that tumors resistant to immune checkpoint inhibitors might be suitable targets for complement-based therapy.
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U2 - 10.4049/jimmunol.2000511
DO - 10.4049/jimmunol.2000511
M3 - Article
C2 - 33158953
AN - SCOPUS:85096815527
SN - 0022-1767
VL - 205
SP - 3218
EP - 3229
JO - Journal of Immunology
JF - Journal of Immunology
IS - 11
ER -