Improving Cancer Immunotherapy responsiveness by inducing Tertiary Lymphoid structures via the activation of innate lymphocytes (ICI-TeL)

In recent years, strategies harnessing tumor-specific T cells have uncovered the potential of immunotherapy in inducing rapid and durable immune control of cancer. However, although some patients can experience dramatic beneficial responses to this type of treatment, the majority of patients do not. Therefore, there is urgent need to develop strategies that target not only neoantigen-specific CD8+ T cells but also synergistic effector cells that have lower thresholds or different pathways of activation.
Emerging data have recently suggested that the efficacy of immune checkpoint inhibitors (ICI) is also largely dependent on the quality, quantity and spatial organization of the immune infiltrate into the tumor and, in this context, it was recently published that Tertiary Lymphoid Structures (TLS) are positively associated to ICI efficacy in solid tumors. TLS are ectopic lymphoid structures that appear in inflamed non-lymphoid tissues as aggregates of immune cells and may be represented by mere aggregates of dendritic cells (DC), T and B cells, or mature TLS with a T zone, containing T lymphocytes and DC, a B zone presenting a germinative center, B lymphocytes, follicular dendritic cells and high endothelium venules. In agreement with their association with ICI efficacy, TLS density is positively correlated to the global immune infiltration of the tumor in CD4 and CD8 T lymphocytes. It was lately reported that the presence of mature TLS can predict ICI efficacy even in solid tumors not expressing PD-L1. At the same time, pretreatments by some conventional anti-cancer therapies may be associated with a better ICI response as well as to TLS frequency. For instance, cisplatin has been recently shown to favor lymphoid aggregated in tumors and improve responsiveness to ICI treatment. Similarly, high dose radiotherapy delivered in a small volume has been reported to increase the efficacy of ICI, at least in certain tumors. However, mechanisms at the basis of this phenomenon remain elusive, thus preventing the precise identification of the interventions able to generate this beneficial effect.
Events leading to the development of TLS are not fully understood and the literature suggests that several paths may lead to the development of TLS. We hypothesize that innate lymphocytes such as innate lymphoid cells and gamma/delta T cells, may be activated by selected cytotoxic therapies and therefore actively participate in the formation of TLS in the tumor bed. We aim to identify antiblastic tretaments currently employed as neo-adjuvant therapy (i.e. before undergoing surgical operation) by retrospectively analyze the frequency and maturation of TLS in tumor samples resected after the neo-adjuvant treatment. We hypothesize that some therapies could cause cell death-associated inflammation and trigger innate lymphocytes for TLS development and organization.
As a whole, this project aims at shedding some light on the mechanisms that can lead to the development of TLS in tumors for identifying therapeutic interventions with abscopal effects able to induce tumor-associated TLS and a better immune response upon ICI treatment.