Abstract
Since the advent of cetuximab, clinical cancer treatment has evolved from the standard, relatively nonspecific chemo- and radiotherapy with significant cytotoxic side effects towards immunotherapeutic approaches with selective, target-mechanism-based effects. Antibody therapies as the most successful form of cancer immunotherapy led to approved treatments for specific cancer types with increased patient survival. Thus, the identification of tumor antigens with high immunogenicity is in central focus now. In this study, we applied computational methods to comprehensively discover overexpressed molecular targets with high therapeutic relevance for clinical, immunotherapeutic cancer treatment in triple-negative breast cancer (TNBC). By actively modeling potential negative side effects utilizing expression data of 29 different, normal human tissues, we were able to develop a highly-specific coverage of TNBC patients with RNA targets. We identified here more than 400 potential tumor-specific antigens suitable for targeted therapy, including several already identified as potential targets for TNBC and other solid tumors. A specific cocktail of MAGEB4, CT83, TLX3, ACTL8, PRDM13 achieved almost 94% patient coverage in TNBC. Overall, these results show that our approach can identify and prioritize TNBC targets suitable for targeted therapy. Therefore, our method has the potential to lead to new and more effective immunotherapeutic cancer treatment.
Highlights
In the last decade, immunotherapy has emerged as a promising approach for cancer treatment
For this goal we classified the expression of all genes of all tissues into highly-expressed, low-expressed or non-expressed, depending on a quantitative mRNA expression threshold determined through multiparametric optimization
In order to take both aspects into consideration for target prioritization, we introduced two indices: a predicted potential adverse events (PPAE) index (IPPAE) and a tumor sample coverage ratio (TSCR) index (ITSCR)
Summary
Immunotherapy has emerged as a promising approach for cancer treatment. Immunotherapeutic strategies against cancer include various approaches. These are ranging from counteracting inhibitory and suppressive mechanisms to stimulating effector mechanisms [1]. Cancer vaccination with tumor antigens as one therapeutic strategy leads to an increase of the ability of the patient’s own immune system to leverage an immune response against cancerous cells [2, 3]. Additional strategies encompass adoptive transfer of ex vivo activated T or natural killing cells mediating tumor cell eradication and the use of monoclonal antibodies manipulating tumor-related signaling or stimulating antitumor immune response to supply co-stimulatory signals to enhance T cell activity [4,5,6]. Substantially increasing the effectivity of immunotherapy in clinical www.oncotarget.com routine, will require the use of appropriate target antigens. The choice of therapeutic targets is a critical factor [7]
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