Recognition of tumor cells by the immune system is a key step in cancer eradication and the use of chemotherapy to boost the anti-tumor immune response is now a promising approach for cancer treatment. Palbociclib is a highly selective inhibitor of CDK4 and CDK6, two key regulators of the cell cycle, and it has recently been approved for clinical usage against ER+ HER2- advanced breast cancer. Even if the molecular mechanisms remain poorly defined, current evidence indicates that the main mode of action of Palbociclib is the induction of cancer cell senescence. As Palbociclib treatment has shown significant tumor regression, it is possible to speculate that the induction of senescence could have wider and additional consequences other than the tumor proliferation arrest only. For this reason, the present proposal aims to elucidate to which extent Palbociclib-induced senescence contributes to the treatment outcome, mainly considering the contribution of the immune surveillance against senescent tumor cells. In particular, the role of Natural Killer (NK) cells in the recognition and killing of senescent tumor cells will be investigated.
To this end, the induction of senescence in response to Palbociclib therapy will be investigated in different types of tumors (breast cancer, melanoma, multiple myeloma, and colorectal cancer). This finding will provide the rationale for studying how senescent tumor cells become more visible to the immune system, especially focusing on the analysis of the stress-induced NK cell-activating ligands expressed on the surface of senescent tumor cells. Moreover, the contribution of the so-called "senescence-associated secretory phenotype" (SASP) to the inflamed milieu of tumor site will be addressed. This point will help to clarify if the stimulation of a local immune reaction driven by senescent cells can eliminate both those cells that have undergone drug-induced senescence and those tumor cells that have bypassed or escaped senescence
First studies paid attention to the proliferation arrest aspect of senescence, highlighting its implications as tumor suppressive mechanism. Nowadays, cellular senescence is considered a more complex program, triggered by a plethora of stimuli during both physiological and pathological conditions. Senescent cells, via SASP, are able to evoke an immune response and to orchestrate important tissue remodeling. The effects of SASP are wide and may achieve even opposite results depending on the cellular context. In this regard, it is of great relevance if senescent cells are recognized and efficiently cleared by the immune system, or they persist in tissues, promoting chronic inflammation and, as a matter of fact, immune suppression, two characteristics of aged tissues. The life span of senescent cells seems to be the compelling factor. "Acute" senescence, when senescent cells are promptly removed from organs, contributes to tissue repair, while "chronic" senescence, due to the persistence of senescent cells in tissues, promotes tissue ageing and inflammation, thus enhancing tumorigenesis. This double aspect of senescence has arisen much interest in uncovering the faith of senescent cells in tissues, especially in cancer settings, as it is clear that the efficacy of certain chemotherapeutic drugs relies on the induction of senescence and pro-senescence therapy is approaching. So, targeting senescent cells is now a major issue of the scientific community. Beside the development of senolytic drugs, the immune surveillance of senescent cells is another aspect that is under investigation.
This point is exactly the focus of the present proposal that explores both the cellular consequences of palbociclib treatment, namely the induction of cellular senescence (task 1), and its immunological implications (task 2). Whether senescent tumor cells are promptly cleared from tumor tissue is of great relevance and the contribution of the immune system has been poorly investigated so far. Experiments of task 2 aim at providing strong evidence of NK cell involvement, thus representing a proof of concept of the immune modulatory effects of certain chemotherapeutic drugs.
The effects of senescent cells on the neighboring cells in terms of tissue homeostasis are little explored and the experiments here proposed, task 3 (SASP-dependent inflammation) and task 4 (Bystander senescence), address this aspect and, in the event of encouraging findings, the relevance of the obtained results might be assessed by the submission of a new proposal focused on in vivo approaches where the involvement of the immune system can be fully addressed.
The idea of making tumor cells prone to NK cell killing is not new, but the findings explored in the present project, specifically that senescent cells are recognized and cleared by NK cells, extend the field of application. NK cell-based anti-cancer therapies are promising and NK cell immunotherapy should be considered as part of a pro-senescence therapy. A combined treatment could be conceived in which tumor cells are forced to senescence and then removed by in vivo boosted NK cells or in vitro activated adoptively transferred NK cells