Key Points
Complement genes are associated with poor prognosis in kidney cancer.
Complement in plasma correlates with response to immune checkpoint inhibitors.
Complement contributes to dysfunction of tumor-infiltrating T cells.
Abstract
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.
Footnotes
This work was supported by the National Cancer Institute, National Institutes of Health (R01CA190209 to M.M.M., P50CA196516 to J.B., and CCSG 5P30CA142543 to T.W.) and the Cancer Prevention and Research Institute of Texas (RP190208 to T.W.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- AF
- Alexa Fluor
- C5aR1
- C5a receptor 1
- ccRCC
- clear-cell RCC
- FB
- factor B
- FD
- factor D
- FH
- factor H
- FI
- factor I
- ICI
- immune checkpoint inhibitor
- IS
- inflammatory subtype
- KO
- knockout
- MDSC
- myeloid-derived suppressor cell
- NIS
- non-IS subtype
- PD-1
- programmed cell death protein 1
- pRCC
- papillary RCC
- RCC
- renal cell carcinoma
- sCD59
- soluble CD59
- TCC
- complement terminal complex
- TIL
- tumor-infiltrating lymphocyte
- TME
- tumor microenvironment
- TNT
- time to next treatment
- UTSW KCP
- University of Texas Southwestern Medical Center Kidney Cancer Program
- WT
- wild-type.
- Received May 6, 2020.
- Accepted September 29, 2020.
- Copyright © 2020 by The American Association of Immunologists, Inc.
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$37.50
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.
Log in using your username and password
In this issue
