Inhibition of dendritic cell maturation by the tumor microenvironment correlates with the survival of colorectal cancer patients following bevacizumab treatment.
Development of bevacizumab has improved survival in colorectal cancer, however, currently there are no biomarkers that predict response to bevacizumab and it is unknown how it influences the immune system in colorectal cancer patients. Dendritic cells are important for the induction of an antitumor immune response; however tumors are capable of disabling dendritic cells and escaping immune surveillance. The aim of this study was to assess the numbers of CD11c+ cells infiltrating tumor tissue and to examine the effects of tumor conditioned media (TCM) and bevacizumab conditioned media (BCM) on dendritic cell maturation and correlate our findings with patient survival. colorectal cancer explant tissues were cultured with or without bevacizumab, to generate BCM and TCM, which were used to treat dendritic cells. CD80, CD86, CD83, CD54, HLA-DR, and CD1d expression was measured by flow cytometry. Interleukin (IL)-10 and IL-12p70 were measured by ELISA. The Cox proportional hazards model was used to associate survival with dendritic cell inhibition. TCM and BCM inhibited lipopolysaccharide (LPS)-induced dendritic cell maturation and IL-12p70 secretion (P < 0.0001), while increasing IL-10 secretion (P = 0.0033 and 0.0220, respectively). Inhibition of LPS-induced CD1d (P = 0.021, HR = 1.096) and CD83 (P = 0.017, HR = 1.083) by TCM and inhibition of CD1d (P = 0.017, HR = 1.067), CD83 (P = 0.032, HR = 1.035), and IL-12p70 (P = 0.037, HR = 1.036) by BCM was associated with poor survival in colorectal cancer patients. CD11c expression was elevated in tumor tissue compared with normal tissue (P < 0.001), but this did not correlate with survival. In conclusion, TCM and BCM inhibit dendritic cells, and this inhibition correlates with survival of colorectal cancer patients receiving bevacizumab.
Translation Rheumatology Research Group, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.
Adriana J
AJ
Michielsen
Sinead
S
Noonan
Petra
P
Martin
Miriam
M
Tosetto
Joseph
J
Marry
Monika
M
Biniecka
Aoife A
AA
Maguire
John M
JM
Hyland
Kieran D
KD
Sheahan
Diarmuid P
DP
O'Donoghue
Hugh E
HE
Mulcahy
David
D
Fennelly
Elizabeth J
EJ
Ryan
Jacintha N
JN
O'Sullivan
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD; D055610:Antigens, CD1d; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000068258:Bevacizumab; D039521:CD11c Antigen; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D006801:Humans; D007136:Immunoglobulins; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D008875:Middle Aged; D009367:Neoplasm Staging; D059016:Tumor Microenvironment / Q000276:immunology*; D000097802:CD83 Antigen
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D055610:Antigens, CD1d; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D039521:CD11c Antigen; D017077:Culture Media, Conditioned; D007136:Immunoglobulins; D016753:Interleukin-10; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D000097802:CD83 Antigen