Immunogenic death of colon cancer cells treated with oxaliplatin

Abstract

Both the pre-apoptotic exposure of calreticulin (CRT) and the post-apoptotic release of high-mobility group box 1 protein (HMGB1) are required for immunogenic cell death elicited by anthracyclins. Here, we show that both oxaliplatin (OXP) and cisplatin (CDDP) were equally efficient in triggering HMGB1 release. However, OXP, but not CDDP, stimulates pre-apoptotic CRT exposure in a series of murine and human colon cancer cell lines. Subcutaneous injection of OXP-treated colorectal cancer (CRC), CT26, cells induced an anticancer immune response that was reduced by short interfering RNAmediated depletion of CRT or HMGB1. In contrast, CDDP-treated CT26 cells failed to induce anticancer immunity, unless recombinant CRT protein was absorbed into the cells. CT26 tumors implanted in immunocompetent mice responded to OXP treatment in vivo, and this therapeutic response was lost when CRT exposure by CT26 cells was inhibited or when CT26 cells were implanted in immunodeficient mice. The knockout of toll-like receptor 4 (TLR4), the receptor for HMGB1, also resulted in a deficient immune response against OXP-treated CT26 cells. In patients with advanced (stage IV, Duke D) CRC, who received an OXP-based chemotherapeutic regimen, the loss-of-function allele of TLR4 (Asp299Gly in linkage disequilibrium with Thr399Ile, reducing its affinity for HMGB1) was as prevalent as in the general population. However, patients carrying the TLR4 loss-of-function allele exhibited reduced progression-free and overall survival, as compared with patients carrying the normal TLR4 allele. In conclusion, OXP induces immunogenic death of CRC cells, and this effect determines its therapeutic efficacy in CRC patients.

Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer

“…The molecular mechanisms that distinguish immunogenic from non-immunogenic cell death have been elucidated and rely on at least three independent events: (i) early surface exposure of calreticulin (ecto-CRT) on stressed cells, (ii) subsequent secretion of ATP and (iii) release of high-mobility group box-1 (HMGB1) and HSPs by dying tumor cells. 1,98 Ecto-CRT favors the engulfment of apoptotic bodies by DCs, whereas HMGB1 and ATP modulate DC-mediated tumor antigen cross-presentation and T-cell polarization. Recently, ATP was shown to also mediate the recruitment and differentiation of myeloid DC to the tumor site following anthracycline treatment in mice.…”

Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments

“…15 Apoptosis occurs ubiquitously in normal tissues and causes 'quiet' cell death that uses phosphatidylserine (PS) as an 'eat-me' signal to be quickly recognized by peripheral APCs. Although apoptotic cell death has been historically considered to be nonimmunogenic, 16 recent studies unraveled that several antineoplastic agents, including doxorubicin, 1,17 oxaliplatin, 18,19 cisplatin, 20 and irradiation, 21,22,23 can trigger immunogenic apoptosis. 2 Mechanistically, the immunogenic apoptotic bodies induced by exposure to doxorubicin are sensed by APCs through their TLR-2/TLR-9-MyD88 signaling pathways.…”

“…25,26,27 The excretion of DAMPs was considered to occur during necrosis under inflammatory and/or pathological conditions. However, DAMPs have recently been reported to be produced from apoptotic cancer cells treated with chemotherapy 1,18 or radiotherapy. 21 …”

“…It has been recently proposed that they can be classified into two categories, type I or II ICD inducers, based on their distinct actions to induce ER stress leading to apoptotic cell death (Tables 2 and 3). 27,28 The majority of ICD inducers such as chemotherapeutic agents (mitoxantrone, 29 anthracyclines, 2,30,31 oxaliplatin, 18,19 and cyclophosphamide 32 ), shikonin, 33,34 the proteasome inhibitor bortezomib, 35 and 7A7 (an epidermal growth factor receptor-specific antibody), 36 cardiac glycosides, 37 and the histone deacetylase inhibitor (vorinostat) 38 are categorized as type I ICD inducers that primarily target cytosolic proteins, plasma membranes, or nucleic proteins. They also induce ER stress via collateral effects.…”

Molecular mechanisms of ATP secretion during immunogenic cell death

“…2,3,13 Of note, most inducers of apoptosis and necrosis fail to trigger ICD. However, a few chemotherapeutics, including anthracyclines, 7,8 OXA, 14 cyclophosphamide, 15 and -to some extent -microtubular inhibitors, 16 as well as cardiac glycosides, [17][18][19] potently do so. 20,21 Such chemicals appear to be particularly efficient at inducing a pre-mortem endoplasmic reticulum (ER) stress response and autophagy.…”