Tumor infiltrating T lymphocytes in colorectal cancer: Tumor-selective activation and cytotoxic activity in situ.
OBJECTIVE
To examine whether tumor-selective infiltration, activation, and cytotoxic activity of tumor infiltrating T lymphocytes (TIL) can be demonstrated in situ in colorectal cancer samples.


BACKGROUND
Recent studies indicated a correlation between the presence of TIL and an improved prognosis in colorectal cancer. However, tumor-selective activation and cytotoxic activity of CD8 TIL in situ in colorectal cancer patients have not yet been examined.


METHODS
Tumor samples from 49 patients and corresponding normal mucosa samples from 23 patients with colorectal cancer (UICC stages II-IV) were examined for TIL. Two-color fluorescence immunohistochemistry and multicolor flowcytometric (FACS) analysis were used for quantification of CD8 T cells and measurement of their activation status (CD69-expression) and cytotoxic activity (CD107a-expression) in situ. Presence of tumor antigen-reactive T cells in tumor, blood, and bone marrow was evaluated by IFN-gamma Elispot analysis.


RESULTS
While absolute numbers of CD8 T cells were similar, CD4 T helper cells were significantly increased in tumor tissue compared with normal mucosa. There was a significantly higher proportion of activated and cytotoxically active CD8 TIL in colorectal cancer compared with normal mucosa. Increased activation, cytotoxic activity, and functional reactivity of TIL were correlated with the presence of functional tumor antigen-reactive T cells in the blood and bone marrow. The proportion of activated TIL decreased significantly with higher tumor stage.


CONCLUSIONS
Tumor-selective activation and cytotoxic activity of CD8 TIL and tumor-selective migration of CD4 T helper cells were demonstrated in colorectal cancer for the first time. Our data support the immunogenicity of colorectal cancer and suggest clinical significance of tumor-specific immune responses.
Koch
Moritz
M
Department of Surgery, University of Heidelberg, Heidelberg, Germany.
Beckhove
Philipp
P
Op den Winkel
Jan
J
Autenrieth
Daniel
D
Wagner
Philipp
P
Nummer
Daniel
D
Specht
Sebastian
S
Antolovic
Dalibor
D
Galindo
Luis
L
Schmitz-Winnenthal
Friedrich H
FH
Schirrmacher
Volker
V
Büchler
Markus W
MW
Weitz
Jürgen
J
D000230:Adenocarcinoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology*; D008297:Male; D009367:Neoplasm Staging
D015703:Antigens, CD