Diet-Induced Obesity Impairs Outcomes And Induces Multi-Factorial Deficiencies In Effector T Cell Responses Following Anti-Ctla-4 Combinatorial Immunotherapy In Renal Tumor-Bearing Mice

Simple SummaryImmunotherapy use has become standard for many patients with advanced kidney cancer; unfortunately, <50% of patients experience durable responses. Mounting evidence suggests that modifiable factors, such as diet and obesity, impact immunotherapy outcomes. Obesity, a major U.S. health epidemic, blunts anti-tumor immunity and promotes tumor growth in multiple preclinical models. However, the full biological impact of obesity on the T cell responses needed to achieve positive immunotherapy outcomes remains unclear. Here, we studied the effects of obesity on T cell responses following combinatorial immunotherapy in a mouse model of kidney cancer. We found that obesity is associated with blunted effector T cell responses, resulting in diminished immunotherapy outcomes. This therapy produces sustained T cell responses and robust tumor control in obese-resistant mice fed the same high-fat diet. Finding ways to amplify T cell responses within renal tumors from hosts with obesity will be critical for achieving optimal immunotherapy outcomes.Associations between modifiable factors and the efficacy of cancer immunotherapies remain uncertain. We found previously that diet-induced obesity (DIO) reduces the efficacy of an immunotherapy consisting of adenovirus-encoded TRAIL plus CpG oligonucleotide (AdT/CpG) in mice with renal tumors. To eliminate confounding effects of diet and determine whether outcomes could be improved in DIO mice, we evaluated AdT/CpG combined with anti-CTLA-4 in diet-matched, obese-resistant (OB-RES) versus DIO tumor-bearing mice. Therapy-treated OB-RES mice displayed effective renal tumor control and sustained CD4(+) and CD8(+) T cell responses. In contrast, therapy-treated DIO mice exhibited progressive tumor outgrowth and blunted T cell responses, characterized by reduced intratumoral frequencies of IFN gamma(+) CD4(+) and CD8(+) T cells. Weak effector T cell responses in therapy-treated DIO mice were accompanied by low intratumoral concentrations of the T cell chemoattractant CCL5, heightened concentrations of pro-tumorigenic GM-CSF, and impaired proliferative capacity of CD44(+)CD8(+) T cells in tumor-draining lymph nodes. Our findings demonstrate that in lean mice with renal tumors, combining in situ T cell priming upstream of anti-CTLA-4 enhances outcomes versus anti-CTLA-4 alone. However, host obesity is associated with heightened immunotherapy resistance, characterized by multi-factorial deficiencies in effector CD4(+) and CD8(+) T cell responses that extend beyond the tumor microenvironment.