Antitumor Immunity Triggered by Melphalan Is Potentiated by Melanoma Cell Surface–Associated Calreticulin

Abstract

Systemic chemotherapy generally has been considered immunosuppressive, but it has become evident that certain chemotherapeutic drugs elicit immunogenic danger signals in dying cancer cells that can incite protective antitumor immunity. In this study, we investigated whether locoregionally applied therapies, such as melphalan, used in limb perfusion for melanoma (Mel-ILP) produce related immunogenic effects. In human melanoma biopsies, Mel-ILP treatment upregulated IL1B, IL8, and IL6 associated with their release in patients' locoregional sera. Although induction of apoptosis in melanoma cells by melphalan in vitro did not elicit threshold levels of endoplasmic reticulum and reactive oxygen species stress associated with danger signals, such as induction of cell-surface calreticulin, prophylactic immunization and T-cell depletion experiments showed that melphalan administration in vivo could stimulate a CD8 þ T cell-dependent protective antitumor response. Interestingly, the vaccination effect was potentiated in combination with exogenous calreticulin, but not tumor necrosis factor, a cytokine often combined with Mel-ILP. Our results illustrate how melphalan triggers inflammatory cell death that can be leveraged by immunomodulators such as the danger signal calreticulin. Cancer Res; 75(8);

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

“…3,53-55 However, in some contexts, specific chemotherapeutics (e.g., melphalan) 56 or targeted therapies (e.g., BRAF V600E inhibitor, vemurafenib) 57 that are not bona fide ICD inducers can evoke a partial and specific subset of these ICD-associated 'eat me' signals/DAMPs and thereby mediate phagocytic clearance with partial immunogenic properties. A very complex interplay between ER stress (centred on the ER stress sensor, protein kinase RNA-like ER kinase (PERK)) 58 and ROS helps in trafficking of ecto-CRT through the conventional secretory pathway.…”

“…65 In some contexts, ecto-HSP90 and ecto-CRT are interchangeable in mediating immunogenicity; 66 while in other cases, ecto-CRT is the superior immunogenic signal. 56 In fact, an in silico analysis suggests that CRT (but not HSP90) possesses close homologues of crucial phagocytosis-assisting motifs. 61 Also, ecto-CRT may correlate better with a phagocytosis increase than ecto-HSP90 in the context of anthracycline-induced ICD.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…158 In both examples, the ability of a specific agent (e.g., oxaliplatin, cyclophosphamide) but not one of its alike (e.g., cisplatin, melphalan) to drive ICD can be explained by the differential activation of ER stress (and hence differential exposure of CALR in the course of RCD). 100,[157][158][159] Well established ICD inducers include commonly employed anticancer chemotherapeutics such as: (1) (6) bortezomib, a proteasomal inhibitor approved for the therapy MM and mantle cell lymphoma (MCL); [171][172][173][174][175][176][177][178][179][180][181] (7) cyclophosphamide, a DNA-alkylating agent approved for use in patients with chronic myeloid leukemia (CML), AML, ALL, chronic lymphocytic leukemia, MM, ovarian carcinoma, breast carcinoma, mycosis fungoides, lymphoma, neuroblastoma, and retinoblastoma; 177,[182][183][184][185][186][187][188][189][190][191] and (8) oxaliplatin, a platinum-derivative licensed for the therapy of advanced colorectal carcinoma in combination with 5-fluorouracil and folinic acid. 156,157,[192][193][194][195][196][197][198] Moreover, there is some evidence that microtubule-targeting agents including taxanes and vinca alkaloids (which are commonly used for the treatment of multiple carcinomas) can stimulate ICD.…”

Immunological metagene signatures derived from immunogenic cancer cell death associate with improved survival of patients with lung, breast or ovarian malignancies: A large-scale meta-analysis

“…Comprehensive preclinical studies have established ICD as an important predictor of potent antitumor immunity. [1][2][3]14,15 ICD is associated with danger signaling pathways mediating the extracellular emission of danger signals like surface calreticulin/heat-shock proteins, secreted ATP and secreted HMGB1. 14,[16][17][18][19][20][21][22][23][24] These danger signals help in activating the innate immune system 14,22 which further boosts the adaptive immunity leading to anti-tumor immunity.…”