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

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.

Translating MSC Therapy in the Age of Obesity

“…Intriguingly, immune checkpoint blockade with an anti-CTLA-4 antibody shows a differential response between obese mice cohorts ( 61 , 62 ). In an orthotopic model of renal cell carcinoma, diet-induced obese (DIO) mice showed no therapeutic anti-tumour response to anti-CTLA-4 therapy.…”

Re-Evaluating the Effects of Obesity on Cancer Immunotherapy Outcomes in Renal Cancer: What Do We Really Know?

“…Notably, evaluations of obese-resistant mice that had been fed the same high fat diet for 20 weeks illustrated that host obesity, and not the high fat diet or its components, was the cause of diminished immunotherapeutic efficacy, because obese-resistant mice responded as well to this combination therapy as did control mice on a low-fat chow diet ( 18 ). More recently, we found that obesity-associated defects in T cell responses extended to the intratumoral CD4+ compartment and CD8+ T cells in tumor-draining lymph nodes in mice with renal tumors that were treated with combinatorial anti-CTLA-4 ( 27 ). In 2021, Kheum et al reported that a combinatorial immunotherapy consisting of anti-PD-1/anti-CTLA-4/anti-LAG-3 was less effective in obese mice fed a Western Diet than in age-matched lean controls on standard diet in both the B16 melanoma and MC38 colon carcinoma models ( 28 ).…”