Prognostic impact of immune response in resectable colorectal liver metastases treated by surgery alone or surgery with perioperative FOLFOX in the randomised EORTC study 40983.
OBJECTIVE
To investigate whether the immune response in colorectal liver metastases is related to progression free survival (PFS) and if this may be influenced by systemic therapy.


METHODS
A retrospective central collection of tumour tissue was organised for the European Organisation for Research and Treatment of Cancer (EORTC) study 40983, where patients with colorectal liver metastases were treated by either resection alone or resection with perioperative FOLFOX. Immunostaining on whole slides was performed to recognise T-lymphocytes (CD3+, CD4+, CD8+), B-lymphocytes (CD20+), macrophages (CD68+) and mast cells (CD117+) inside the tumour, at the tumour border (TNI) and in normal liver tissue surrounding the tumour (0.5-2mm from the TNI). Immunological response was compared between treatment arms and correlated to PFS.


RESULTS
Tumour tissue and immune response profiles were available for 82 resected patients, 38 in the perioperative chemotherapy arm and 44 in the surgery alone arm. Baseline patient and disease characteristics were similar between the treatment arms. In response to chemotherapy, we observed increased CD3+ lymphocyte and mast cell counts inside the tumour (p<0.01), lower CD4+ lymphocytes in the normal liver tissue (p=0.02) and lower macrophage counts in normal tissue (p<0.01) and at the TNI (p=0.02). High number of CD3+ lymphocyte and mast cells, and high T-cell score were correlated with tumour regression grade (TRG). Prolonged PFS correlated with the presence of mast cells in the tumour (9.8 versus 16.5 months, Hazard ratio (HR) 0.54 p=0.03), higher CD3+ lymphocyte count at the TNI (10.8 versus 22.8 months, HR 0.57, p=0.03) and T-cell score >2 (10.8 versus 38.6 months, HR 0.51, p=0.04).


CONCLUSIONS
Our analyses in the context of a randomised study suggest that chemotherapy influences immune cell profiles, independent of patient characteristics. Immune responses of lymphocytes and mast cells were associated with pathological response to chemotherapy and to increased PFS. High CD3+ lymphocytes at the tumour front and intratumoural mast cells appear to be prognostic for patients with colorectal liver metastases.
EORTC headquarters, Brussels, Belgium; The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: eriktanis@gmail.com.
Erik
E
Tanis
CHU Ambroise Pare, Paris, France.
Catherine
C
Julié
CHU Ambroise Pare, Paris, France.
Jean-Francois
JF
Emile
EORTC headquarters, Brussels, Belgium.
Murielle
M
Mauer
CHU Ambroise Pare, Paris, France.
Bernard
B
Nordlinger
Universitatsklinikum Dresden, Dresden, Germany.
Daniela
D
Aust
University of Geneva, Geneva, Switzerland.
Arnaud
A
Roth
Caritas Klinikum, Saarbrucken, Germany.
Manfred P
MP
Lutz
Rudolfstiftung Hospital, Vienna, Austria.
Thomas
T
Gruenberger
Rudolfstiftung Hospital, Vienna, Austria.
Fritz
F
Wrba
Haukeland University Hospital, Bergen, Norway.
Halfdan
H
Sorbye
Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany.
Wolf
W
Bechstein
Charité Campus Buch/ECRC and MDC, Berlin, Germany.
Peter
P
Schlag
Dr. Horst Schmidt Kliniken, Wiesbaden, Germany.
Annette
A
Fisseler
The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Theo
T
Ruers
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D018951:Antigens, CD20 / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D017024:Chemotherapy, Adjuvant / Q000379:methods; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007107:Immune System / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002955:Leucovorin / Q000008:administration & dosage; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011379:Prognosis; D012189:Retrospective Studies; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D000097382:CD68 Molecule
D015703:Antigens, CD; D018951:Antigens, CD20; D015214:Antigens, Differentiation, Myelomonocytic; D017252:CD3 Complex; D005472:Fluorouracil; D002955:Leucovorin; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C067980:CD68 antigen, human; D000097382:CD68 Molecule
B-lymphocytes; Chemotherapy response; Colorectal liver metastases; Immune profile; Macrophages; Mast cells; T-lymphocytes