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2016 ; 4
(ä): 23
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Targetless T cells in cancer immunotherapy
#MMPMID27096099
Thor Straten P
; Garrido F
J Immunother Cancer
2016[]; 4
(ä): 23
PMID27096099
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Attention has recently focused on new cancer immunotherapy protocols aiming to
activate T cell mediated anti-tumor responses. To this end, administration of
antibodies that target inhibitory molecules regulating T-cell cytotoxicity has
achieved impressive clinical responses, as has adoptive cell transfer (ACT) using
expanded tumor infiltrating lymphocytes (TIL) or genetically modified cytotoxic T
cells. However, despite clear clinical responses, only a fraction of patients
respond to treatment and there is an urgent call for characterization of
predictive biomarkers. CD8 positive T cells can infiltrate tumor tissues and
destroy HLA class I positive tumor cells expressing the specific antigen. In
fact, current progress in the field of cancer immune therapy is based on the
capacity of T cells to kill cancer cells that present tumor antigen in the
context on an HLA class I molecule. However, it is also well established that
cancer cells are often characterized by loss or down regulation of HLA class I
molecules, documented in a variety of human tumors. Consequently, immune therapy
building on CD8 T cells will be futile in patients harboring HLA class-I negative
or deficient cancer cells. It is therefore mandatory to explore if these
important molecules for T cell cytotoxicity are expressed by cancer target cells.
We have indications that different types of immunotherapy can modify the tumor
microenvironment and up-regulate reduced HLA class I expression in cancer cells
but only if the associated molecular mechanisms is reversible (soft). However, in
case of structural (hard) aberrations causing HLA class I loss, tumor cells will
not be able to recover HLA class I expression and as a consequence will escape
T-cell lysis and continue to growth. Characterization of the molecular mechanism
underlying the lack or downregulation of HLA class I expression, seems to be a
crucial step predicting clinical responses to T cell mediated immunotherapy, and
possibly aid the selection of strategies that could condition patients for
response. Thus, characterization of HLA expression by cancer cells could
therefore represent an important predictive marker for immunotherapy of cancer.
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