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Chemotherapy‐induced immunogenic modulation of tumor cells enhances killing by cytotoxic T lymphocytes and is distinct from immunogenic cell death
Author(s) -
Hodge James W.,
Garnett Charlie T.,
Farsaci Benedetto,
Palena Claudia,
Tsang KwongYok,
Ferrone Soldano,
Gameiro Sofia R.
Publication year - 2013
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.28070
Subject(s) - docetaxel , immunogenic cell death , cytotoxic t cell , cancer research , immune system , calreticulin , immunology , programmed cell death , antigen , biology , chemotherapy , medicine , immunotherapy , apoptosis , in vitro , microbiology and biotechnology , biochemistry , endoplasmic reticulum
Certain chemotherapeutic regimens trigger cancer cell death while inducing dendritic cell maturation and subsequent immune responses. However, chemotherapy‐induced immunogenic cell death (ICD) has thus far been restricted to select agents. In contrast, several chemotherapeutic drugs modulate antitumor immune responses, despite not inducing classic ICD. In addition, in many cases tumor cells do not die after treatment. Here, using docetaxel, one of the most widely used cancer chemotherapeutic agents, as a model, we examined phenotypic and functional consequences of tumor cells that do not die from ICD. Docetaxel treatment of tumor cells did not induce ATP or high‐mobility group box 1 (HMGB1) secretion, or cell death. However, calreticulin (CRT) exposure was observed in all cell lines examined after chemotherapy treatment. Killing by carcinoembryonic antigen (CEA), MUC‐1, or PSA‐specific CD8 + CTLs was significantly enhanced after docetaxel treatment. This killing was associated with increases in components of antigen‐processing machinery, and mediated largely by CRT membrane translocation, as determined by functional knockdown of CRT, PERK, or CRT‐blocking peptide. A docetaxel‐resistant cell line was selected (MDR‐1 + , CD133 + ) by continuous exposure to docetaxel. These cells, while resistant to direct cytostatic effects of docetaxel, were not resistant to the chemomodulatory effects that resulted in enhancement of CTL killing. Here, we provide an operational definition of “immunogenic modulation,” where exposure of tumor cells to nonlethal/sublethal doses of chemotherapy alters tumor phenotype to render the tumor more sensitive to CTL killing. These observations are distinct and complementary to ICD and highlight a mechanism whereby chemotherapy can be used in combination with immunotherapy.