Introduction
tumor
TUMOR, RECRUITMENT
Immune checkpoint inhibitors (ICI) are drugs targeting regulatory pathways in T cells to enhance antitumor immune responsesIn this scenario, an active area of biomedical research aims to identify combinatorial approaches that could improve even the early phases of developing the antitumor response. Mechanistically, these new immunotherapy regimens aim at achieving one or more of three main effects thought to be crucial for overcoming resistance to immune intervention: (i) fostering the cross-talk between innate and adaptive arms of the immune system, (ii) promoting the recruitment of functional T cells at the tumor site, and (iii) counteracting recruitment/function of immunosuppressive cells.Among promising agents that may play a role in ICI combinations there are the hypomethylating agent (HMA) due to their immunomodulatory activity on tumor cellsDespite these initial promising clinical applications of the HMA guadecitabine combined with ICI, the further development of these combinatorial approaches requires the understanding of the biological mechanisms underlying the response and resistance to this specific type of epigenetic immunomodulation. The NIBIT-M4 study was a single-arm trial, therefore, in principle, such design prevents the possibility to achieve a sound disentanglement of the contribution of ipilimumab vs. the contribution of guadecitabine to the overall clinical activity.Here we show that an advanced integrative systems biology approach, focusing on genomic, transcriptional, and methylation landscape analysis of baseline and on-treatment tumor tissues can shed light on the mechanisms of action of the two agents and on the resistance mechanisms likely impacting the ICI vs. the demethylating agent. In fact, first, we asked whether responder patients show differential enrichment of genomic features vs. non-responder patients. In particular, we analyze the effects of guadecitabine in the cases harboring mutations in its target genes. We also explored the promotion of expression of retroviral sequences and of repetitive elements that represent the mechanistic signature of immunomodulation by guadecitabine. We tested a combinatorial index for predicting long-term clinical benefit by integrating transcriptional information on the development of adaptive immunity, the Immunological Constant of Rejection (ICR)