UNDERPINNINGS OF CD8 T CELL ACTIVATION DURING IMMUNOSENESCENCE FOR CANCER IMMUNOTHERAPIES

Abstract

Immunotherapy has transformed cancer treatment, yet its efficacy remains variable, particularly in the context of aging, where immunosenescence impairs CD8+ T cell function. Aging is a major risk factor for poor responses to infection, therapy, and cancer. Critical gaps remain understanding how early CD8⁺ T cell activation states are regulated during aging. This thesis investigates the interplay between the CD38–NAD⁺ metabolic axis, early CD8⁺ T cell activation, and the ligandome of solid and hematological malignancies, that disproportionately affect older population. We first analyzed patients with pulmonary-only metastatic prostate cancer (PO-mPCa), a rare clinical cohort associated with favorable prognosis. Using an in-house developed pipeline, we defined the human leukocyte antigen (HLA) class I-restricted neoepitope landscape in these patients. This revealed a distinct neoepitope repertoire enriched in immunodominant peptides of optimal length, suggesting that unique HLA-neoepitope interactions may underlie their favorable disease course and providing a rationale for neoantigen-guided interventions. Next, we examined how immunosenescence reprograms early CD8⁺ T cell differentiation. We identified a transient pre-effector (TPE) (P4, CD44lowCD62Llow) that emerges rapidly after activation, functions within an innate-like timeframe, and bridges naïve to effector states. Strikingly, P4 frequencies declined with age, but residual cells were enriched for CD38 expression. Functional assays revealed that type I interferons can restore P4 effector capacity through IFNAR1-dependent bystander activation, rescue NAD⁺ and adenosine-mediated suppression. Finally, we investigated the ligandome of mantle cell lymphoma (MCL), integrating in vitro, in vivo, and patient-derived samples. Immune pressure and oncolytic virus therapy dynamically remodeled the HLA ligandome, dynamically altering predicted neoepitope candidates. Chemotherapy-treated patient samples further revealed reduced mutational and neoepitope burden, consistent with successful immune clearance. Overall, this thesis delineates how aging and therapy reshape the CD8⁺ T cell and tumor antigen landscapes, establishing the CD38–NAD⁺ axis and early P4 differentiation state as key modulators of immune competence. These insights provide both mechanistic underpinnings of immunosenescence and actionable strategies to optimize cancer immunotherapies across solid and hematological malignancies.