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 SUMMARY: Immunotherapy 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. ABSTRACT: 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 IFNγ(+) 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.