These data argue that anti-tumor immune responses during or post-treatment are non-existent, ineffective or overcome by immune evasive mechanisms. Definitively, tumor repopulation during cytotoxic therapy regimens and the development of radio or chemoresistance remain a major cause of treatment failure 19, 20, 26. Similarly, extensive evidence supports the notion that dead cells can promote immunological tolerance or drive inflammatory responses that fuel tumor progression 22, 23, 24, 25. Various mechanisms have been proposed to explain the latter 19, 20, among which is the Révész effect, a long-appreciated phenomenon by which lethally-irradiated cancer cells stimulate the growth of live cells 21. In sharp contrast with these findings supporting immune-mediated benefit of cytotoxic agents, preclinical and clinical data indicate that these treatments can paradoxically have detrimental protumorigenic effects. In non-small cell lung cancer (NSCLC) 12, 13, urothelial cancer 14 and triple negative breast cancer (TNBC) 15, 16, 17, 18, among other cancer types, combinations of CTX and ICB are already approved and used as first-line treatments 11. Accordingly, various studies exposed the benefit of combining immune checkpoint inhibitors and cytotoxic therapy 8, 9, 10 and numerous clinical trials are currently evaluating these combinations across cancer types 11. Moreover, some cytotoxic agents, often referred to as immunogenic cell death (ICD) inducers, have been shown to be more efficient than others at promoting immune-mediated control 3. Certain modalities of cell death can drive tumor-specific T cell responses and growth control through exposure of cancer cell-associated target antigens and stimulation of antigen presenting cells 2, 5, 6, 7. These observations are consistent with the view that release of damage-associated molecular patterns (DAMPs) 4 and production of inflammatory mediators by dying cancer cells 5, 6 can boost cancer-restraining immune responses. Hallmark cellular and molecular mediators of anti-cancer immune responses are indispensable for, and correlate with, the efficacy of cytotoxic therapy in animal models and human cancers, respectively 3. In addition to their direct killing of cancer cells, numerous studies have also highlighted a major role for the immune system in mediating the efficacy of these therapies 2, 3. Tumor shrinkage following CTX and radiotherapy has been largely attributed to the damaging effects of these cytotoxic agents on rapidly proliferating cancer cells. Despite these advances, cytotoxic therapies, such as chemotherapy (CTX) or radiotherapy, remain the standard of care for most unresectable or advanced malignancies, including in adjuvant and neoadjuvant settings. Immune checkpoint blockade (ICB) therapies targeting the cytotoxic T lymphocyte-associated antigen-4 and programmed cell death (PD)−1 pathways have transformed the landscape of cancer treatment 1. Our findings suggest COX-2/PGE 2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE 2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E 2 (PGE 2) production in cancer cells with pre-existing COX-2 activity. The underlying mechanisms dictating these opposing outcomes are poorly defined. Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression.
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