Complement c5a receptor facilitates cancer metastasis by altering T-cell responses in the metastatic niche.
The impact of complement on cancer metastasis has not been well studied. In this report, we demonstrate in a preclinical mouse model of breast cancer that the complement anaphylatoxin C5a receptor (C5aR) facilitates metastasis by suppressing effector CD8(+) and CD4(+) T-cell responses in the lungs. Mechanisms of this suppression involve recruitment of immature myeloid cells to the lungs and regulation of TGFβ and IL10 production in these cells. TGFβ and IL10 favored generation of T regulatory cells (Treg) and Th2-oriented responses that rendered CD8(+) T cells dysfunctional. Importantly, pharmacologic blockade of C5aR or its genetic ablation in C5aR-deficient mice were sufficient to reduce lung metastases. Depletion of CD8(+) T cells abolished this beneficial effect, suggesting that CD8(+) T cells were responsible for the effects of C5aR inhibition. In contrast to previous findings, we observed that C5aR signaling promoted Treg generation and suppressed T-cell responses in organs where metastases arose. Overall, our findings indicated that the immunomodulatory functions of C5aR are highly context dependent. Furthermore, they offered proof-of-concept for complement-based immunotherapies to prevent or reduce cancer metastasis.
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Surya Kumari
SK
Vadrevu
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Navin K
NK
Chintala
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Sharad K
SK
Sharma
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Priya
P
Sharma
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Clayton
C
Cleveland
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Linley
L
Riediger
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Sasikanth
S
Manne
Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Queensland, Australia.
David P
DP
Fairlie
Bioreference Laboratories, Elmwood Park; Regional Cancer Care Associates, Hackensack, New Jersey; and.
Wojciech
W
Gorczyca
Clinical Pathology Associates, Abilene, Texas;
Othon
O
Almanza
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center;
Magdalena
M
Karbowniczek
Authors' Affiliations: Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Science Center; maciej.markiewski@ttuhsc.edu.
Maciej M
MM
Markiewski
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D015936:Complement C5a / Q000276:immunology; D005260:Female; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000276:immunology / Q000556:secondary; D008168:Lung / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009362:Neoplasm Metastasis; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
C556062:IL10 protein, mouse; D044087:Receptor, Anaphylatoxin C5a; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D015936:Complement C5a