Exploring the effects of T cell senescence in RCC and HGSOC.

Abstract

e16542 Background: T cell senescence is an emerging mechanism of immune dysfunction characterized by impaired proliferation and reduced effector capacity. Although stressors such as obesity and chemotherapy can promote senescence, their effects on T cell senescence are less clear, as are the downstream consequences for therapy outcomes. Obesity increases the risk of both renal cell carcinoma (RCC) and high-grade serous ovarian cancer (HGSOC). We have reported that obesity is associated with poor outcomes in advanced RCC patients receiving anti–PD-1 immunotherapy, but the mechanistic basis for this observation remains unclear. In HGSOC, standard of care remains neoadjuvant chemotherapy followed by tumor resection. We hypothesized that obesity and chemotherapy independently promote T cell senescence, thereby decreasing responsiveness to standard of care therapies. Methods: To investigate the contribution of T cell senescence across these tumor types, we profiled intratumoral T cell senescence in RCC using diet-induced obese (DIO) and lean tumor-bearing mice by flow cytometry and evaluated human RCC tumor specimens from patients with or without obesity using COMET multiplex immunofluorescence. In parallel, we also evaluated intratumoral T cell senescence in HGSOC using COMET multiplex immunofluorescence in women with or without obesity using matched pre- and post-neoadjuvant chemotherapy to assess potential changes in intratumoral T cell senescence. Results: RCC tumors from patients with obesity exhibited increased senescent T cell populations compared to lean patients. Similarly, tumors from DIO mice demonstrated increased expression of senescence-associated markers, particularly among CD4+ T cells. Importantly, blockade of KLRG1, an inhibitory receptor associated with senescence and reduced T cell function, in combination with anti–PD-1 restored therapeutic responsiveness in DIO mice and improved outcomes to levels comparable to lean mice treated with anti–PD-1 alone. Conclusions: Collectively, these findings support a role for T cell senescence in impaired responses to therapy and highlight targeting senescence-associated pathways, including KLRG1 blockade, as a potential strategy to improve anti-tumor immunity, a strategy that could be applied across obesity-associated cancers.