Abstract
Immunogenic cell death (ICD) is clinically relevant because cytotoxicants that kill malignant cells via ICD elicit anticancer immune responses that prolong the effects of chemotherapies beyond treatment discontinuation. ICD is characterized by a series of stereotyped changes that increase the immunogenicity of dying cells: exposure of calreticulin on the cell surface, release of ATP and high mobility group box 1 protein, as well as a type I interferon response. Here, we examined the possibility that inhibition of an oncogenic kinase, anaplastic lymphoma kinase (ALK), might trigger ICD in anaplastic large cell lymphoma (ALCL) in which ALK is activated due to a chromosomal translocation. Multiple lines of evidence plead in favor of specific ICD-inducing effects of crizotinib and ceritinib in ALK-dependent ALCL: (i) they induce ICD stigmata at pharmacologically relevant, low concentrations; (ii) can be mimicked in their ICD-inducing effects by ALK knockdown; (iii) lose their effects in the context of resistance-conferring ALK mutants; (iv) ICD-inducing effects are mimicked by inhibition of the signal transduction pathways operating downstream of ALK. When ceritinib-treated murine ALK-expressing ALCL cells were inoculated into the left flank of immunocompetent syngeneic mice, they induced an immune response that slowed down the growth of live ALCL cells implanted in the right flank. Although ceritinib induced a transient shrinkage of tumors in lymphoma-bearing mice, irrespective of their immunocompetence, relapses occurred more frequently in the context of immunodeficiency, reducing the effects of ceritinib on survival by approximately 50%. Complete cure only occurred in immunocompetent mice and conferred protection to rechallenge with the same ALK-expressing lymphoma but not with another unrelated lymphoma. Moreover, immunotherapy with PD-1 blockade tended to increase cure rates. Altogether, these results support the contention that specific ALK inhibition stimulates the immune system by inducing ICD in ALK-positive ALCL.
Highlights
Cancer has been conceived as an essentially cell autonomous disease [1] until it became clear that cancer cells need to elude immune control to generate invasive tumors [2]
We show that effects of anaplastic lymphoma kinase (ALK) inhibitors with respect to the induction of the such tyrosine kinase inhibitor (TKI) can trigger Immunogenic cell death (ICD) through on-target effects
The most recent clinically approved ICD inducers are lurbinectedin, an inhibitor of transcription that was FDA-approved for the treatment of small-cell lung cancer in June 2020 [46], as well as an anti-BCMA antibody conjugated to a microtubular poison that was FDA-approved in August 2020 for the treatment of relapsed or refractory multiple myeloma [47]
Summary
Cancer has been conceived as an essentially cell autonomous disease (caused by [epi]genetically unstable cancer cells that proliferate, invade and disseminate) [1] until it became clear that cancer cells need to elude immune control to generate invasive tumors [2]. Genetic tumor aberrations guide immune escape, recruiting immunosuppressive macrophages or myeloid-derived suppressor cells [5, 6] or hiding tumor cells from recognition (downregulating class I major histocompatibility complex) [7]. In this context, an authentic paradigm shift has occurred over the past decade. Immune checkpoint inhibitors that target the immunosuppressive PD-1/PD-L1 interaction are being approved for ever more oncological indications, across a wide spectrum of malignant disease [9,10,11,12]
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