Therapeutic strategies to restore intratumoral immune activity in human cancer

Abstract

Dysfunctional T cells at the tumor site represent a critical frontier in tumor immunity. This thesis investigates strategies to reinvigorate these cells, using ex vivo tumor explant models to assess their responsiveness to immune checkpoint blockade (ICB) and Interleukin-2 (IL-2). A central finding is that both CD4+ and CD8+ T cells can mount responses to anti-PD-1 therapy in human tumor tissue, though these responses are largely mediated through increased translational capacity rather than broad transcriptional rewiring, consistent with the fixed epigenetic state of late-dysfunctional T cells. Due to limited response rates of PD-1 blockade alone, this work also explores complementary strategies to overcome resistance. IL-2 signaling demonstrated the capacity to activate T cells in tumors unresponsive to ICB, while a novel cis-targeted CD8-IL-2 variant showed promise in broadly arming dysfunctional CD8+ T cells with enhanced effector function, potentially disrupting their epigenetic rigidity. Analysis of pre and post ICB samples reinforced the potential relevance of dysfunctional T cells as predictors of immunotherapy response, even in tumor types with low mutational burden. Together, these findings advance our understanding of intratumoral T cell biology and highlight the potential importance of intratumoral dysfunctional T cells.