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Suppression of established hepatocarcinoma in adjuvant only immunotherapy: alum triggers anti-tumor CD8+ T cell response- Scientific Reports 5, Article number: 17695 (2015)
- doi:10.1038/srep17695
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Received:23 July 2015Accepted:04 November 2015Published online:09 December 2015
AbstractDendritic cell-based immunotherapy is a new weapon in our battle against malignancies in human. Recent trials in human and research work in model animals have shown various degrees of success, suggesting its great potential for clinical use. While protocols vary, a common scheme in this category of treatment involves activation of dendritic cells, with the purpose of increasing antigen presentation and cellular immunity. Therefore, proper use of immune adjuvant is a central subject of study. We report here an unexpected finding that injection of alum, the most widely used human adjuvant, into mice carrying H22 hepatocarcinoma resulted in a significant reduction of tumor growth with extended animal survival. This effect was associated with an increased specific CD8+ T cell activation and an inflammatory environment, yet with minimal overt side effects. Our finding suggests that use of adjuvant alone in certain established tumors can invoke protective host immune activation against the same target, which may be of value in our development of new cancer immunotherapies.
IntroductionImmunotherapy of cancer has been regarded as one of the biomedical breakthroughs in recent years1. The goal of immunotherapy is to invoke host immune responses to control and in optimal cases to eradicate the neoplasm, which in contrast to conventional tumor treatment is safe with fewer side effects. Currently there are over one thousand clinical trials under this category being carried out2 (data extracted from www.clinicaltrials.gov). Among them, adoptive cell transfer (ACT), immune checkpoint blockage and dendritic cell-based vaccines are most intensely studied3,4,5.
Unlike prophylactic vaccination whereby host immune response is induced in preparation of future encounters of infectious agents, cancer immunotherapy is to break the state of tolerance towards antigens errantly present or overly expressed in tumor cells6. ACT involves in vitro expansion of host T cells stimulated by tumor antigens, in the absence of in vivo inhibitory factors, and reinfusion of these cells into the host for cytolysis and apoptosis induction of the tumor7,8. More recent efforts apply biomedical engineering technologies through which tumor antigen- specific receptors are expressed on the infused lymphocytes for more robust recognition9,10. Immune checkpoint blockage takes advantage of some common tactics used by cancerous tissues to shield themselves from immune detection, particularly via signaling of cell surface negative immune regulators. Antibodies against CTLA-4 have been used successfully in treating metastatic melanoma11,12,13. Blocking PD-1/PD-L1 signaling has also shown great efficacy in treating papilloma virus-induced malignant lesions and a list of other solid tumors3,14. While these protocols hold great potential, they are not without peril. ACT suffers from difficulty in antigen identification and technical challenges in immune cell expansion15,16, check point blockage is only applicable in a limited number of solid tumors10 and is often associated with autoimmunity, including colitis and dermatitis17,18. DC-based immune therapy, which aims at increasing the intensity and breadth of antigen presentation, remains a valid alternative.
Dendritic cells constantly present host endogenous antigens to T cells that in the absence of danger signal serves as a mechanism of peripheral tolerance induction19. Tumor antigens are presented in this context. In the tumor environment, additional negative regulations are often present, including tumor-associated macrophages and suppressive cytokines such as TGFβ20,21,22. In this case, adjuvant becomes critically important in triggering activation of DCs23. Effectuating through TLRs/NLRs, phagocytosis induction, or DC membrane alteration, adjuvants often induce strong DC activation, leading to robust antigen presentation, expression of costimulatory molecules and secretion of inflammatory cytokines24,25,26. DC-based vaccines can be roughly divided into three categories. DCs isolated from the host or/and expanded in vitro can be loaded with tumor antigens (epitope peptides or autologous tumor lysates) in the presence of adjuvant, and reinfused into the host27,28. A more targeted approach uses tumor cells that are engineered to express GM-CSF to specifically attract DCs in vivo29. More recently, tumor antigens have been fused to antibodies that specifically recognize DC surface markers, such as DEC205, DNGR1, CD40 etc. for better targeting, often achieving immune response in the absence of additional adjuvant30,31,32. The most basic/passive protocol uses tumor antigens admixed with adjuvant in hopes that DCs would capture and present those antigens upon stimulation33,34. Conceptually, since antigens from established tumors are constantly presented by DCs, leading to immune tolerance in the absence of DC activation, proper stimulation of DCs may in theory reverse the inhibition and invoke tumor immunity.
We report here an unexpected finding that in Balb/c mice with an established H22 hepatocarcinoma, a protocol of repeated alum injections invoked a tumor-specific immune response that significantly inhibited tumor growth and mortality. This response was critically dependent on the adoptive immune system, particularly CD8+ T cells, and to a lesser extent neutrophils. Importantly, this protocol triggered little systemic inflammation and tissue damage. Our results therefore suggest that administrating adjuvant alone in tumor-bearing hosts may lead to tumor suppression, likely via nonspecific activation of DCs. Since alum is a well-tolerated adjuvant, our outcomes therefore implicate its potential use in tumor treatment.
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发表于 2015-12-15 20:41
