Maresca, Daniela Claudia (2025) The role of Innate Lymphoid Cells (ILCs) in cancer. [Tesi di dottorato]

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Abstract

Urogenital malignancies, including prostate cancer (PCa) and bladder cancer (BCa), represent a major global health burden, particularly among aging male populations. Despite notable advances in diagnosis and therapeutic strategies, both diseases remain associated with high morbidity and mortality, highlighting the need for innovative therapeutic approaches. Increasing evidence defined immune cells as critical orchestrators of the tumor microenvironment in different types of cancer including urogenital cancers. In this context, innate lymphoid cells (ILCs), a heterogeneous family of lymphocytes lacking antigen-specific receptors, can exert dichotomous roles in cancer, promoting either tumor suppression or progression depending on their subset composition, activation state, and the local cytokine milieu. In PCa, peripheral immune profiling reveals a stage-dependent shift toward a predominance of pro-tumoral type-2 ILCs (ILC2s) accompanied by a reduction in anti-tumoral type-1 ILCs (ILC1s). This imbalance correlates with elevated prostate-specific antigen (PSA) levels and is characterized by heightened ILC2 activity, including robust secretion of IL-13 and IL-5. Concomitantly, circulating levels of ILC2-activating mediators such as IL-33, IL-18, and PGD₂ are increased, suggesting upstream drivers of this skewed immune landscape. Functional assays demonstrate that ILC2-derived IL-13 enhances PCa cell migration and invasion, supporting a direct role in disease progression. In BCa, a comparable immunological pattern emerges, with ILC2s being reprogrammed toward a pro-tumoral phenotype. Among the upstream drivers of this shift, nerve growth factor (NGF) has been identified as a potent activator, engaging the high-affinity TrkA receptor on ILC2s to stimulate type-2 cytokine release and promote regulatory T cell (Treg) expansion. In the bladder tumor microenvironment, NGF-producing mast cells accumulate, sustaining ILC2 activation and thereby facilitating immune evasion. Pharmacological blockade of the NGF–TrkA axis in orthotopic BCa models prolongs survival. Clinically, elevated NGF concentrations inversely correlate with survival in ILC2-enriched tumors, underscoring the translational relevance of this pathway. Collectively, these findings highlight ILC2s as pivotal immunoregulatory nodes in both prostate and bladder cancers. Targeting upstream activators—such as IL-33, PGD2, or NGF—and rebalancing the ILC1/ILC2 axis may represent promising strategies to improve outcomes, particularly in patients resistant to current immunotherapies.

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