Glioblastoma stem cells as carriers of tumour memory: a strategy for personalised immunotherapy using tumour-infiltrating lymphocytes

Abstract

Glioblastoma (GB) remains one of the most aggressive brain tumours, with a median survival of 15 months, largely due to resistance towards available anti-cancer therapies, including cutting-edge immunotherapy. Growing evidence indicates involvement of cancer stem cells (CSCs) in escalating resistance against existing treatment modalities due to their phenotypic plasticity, elevated expression of drug-resistance pumps, and immunomodulatory behaviour. Such oncogenic consequences are regulated by several epigenetic reprogramming events that are pivotal in retaining adaptive traits associated with CSC-mediated therapy resistance and subsequent oncogenic progression. In this review, we consider such epigenetic consequences as “tumour memory” and try to shed light on the therapeutic vulnerabilities by targeting CSCs — the “carriers of tumour memory” — via immune interventions in GB. Interestingly, immune-based anti-cancer therapies are coming to the forefront of cancer research, where T lymphocytes are immunologically boosted to attack tumour cells. However, in reality, several constraints burden such procedures. Contextually, the GB microenvironment, dominated by bone marrow-derived cells, reprograms infiltrating immune cells into suppressor phenotypes, creating a “cold” immune landscape. The only zone where functionally active lymphocytes are preserved is the invasive margin of the tumour, where they undergo exhaustion along the TPE → TEX axis but retain proliferative potential. On this basis, we introduce the concept of “invasive margin lymphocytes” (IMLs), of which stem-like memory T cells (TSCM) are indispensable for long-term immunological protection, as they have unique proliferative potential and ability for long-term persistence. Incidentally, such TSCMs have striking similarities with CSCs, as both cell types employ evolutionarily conserved mechanisms of the WNT/β-catenin signalling pathway, hierarchical organisation, and DNA repair systems. Therefore, understanding CSC–TSCM bidirectional cross-talk could provide a heuristic basis for developing personalised TIL-based therapy aimed at suppressing the hierarchically organised CSC population and overcoming CSC-guided immunotherapy resistance. Drawing conceptual parallels between GB CSCs and TSCM, here in this review, we propose a three-stage therapeutic strategy: precision cytoreduction of the invasive margin, “warming up” the microenvironment using cancer vaccines and pharmacological agents, as well as adoptive transfer of TILs derived from the IML pool to ensure durable disease control.