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
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 el...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-05-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/10/2295 |
| _version_ | 1797534536939077632 |
|---|---|
| author | William J. Turbitt Shannon K. Boi Justin T. Gibson Rachael M. Orlandella Lyse A. Norian |
| author_facet | William J. Turbitt Shannon K. Boi Justin T. Gibson Rachael M. Orlandella Lyse A. Norian |
| author_sort | William J. Turbitt |
| collection | DOAJ |
| description | 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<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup> CD4<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> 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<sup>+</sup> and CD8<sup>+</sup> T cell responses that extend beyond the tumor microenvironment. |
| first_indexed | 2024-03-10T11:31:58Z |
| format | Article |
| id | doaj.art-a90b3477615e44e4a2cbd0d465a684e0 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:31:58Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-a90b3477615e44e4a2cbd0d465a684e02023-11-21T19:13:16ZengMDPI AGCancers2072-66942021-05-011310229510.3390/cancers13102295Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing MiceWilliam J. Turbitt0Shannon K. Boi1Justin T. Gibson2Rachael M. Orlandella3Lyse A. Norian4Department of Nutrition Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USAGraduate Biomedical Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USAGraduate Biomedical Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USAGraduate Biomedical Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USADepartment of Nutrition Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL 35233, USAAssociations 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<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup> CD4<sup>+</sup> and CD8<sup>+</sup> 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<sup>+</sup>CD8<sup>+</sup> 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<sup>+</sup> and CD8<sup>+</sup> T cell responses that extend beyond the tumor microenvironment.https://www.mdpi.com/2072-6694/13/10/2295diet-induced obesitycancer therapyimmunotherapyT cells |
| spellingShingle | William J. Turbitt Shannon K. Boi Justin T. Gibson Rachael M. Orlandella Lyse A. Norian 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 Cancers diet-induced obesity cancer therapy immunotherapy T cells |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | diet-induced obesity cancer therapy immunotherapy T cells |
| url | https://www.mdpi.com/2072-6694/13/10/2295 |
| work_keys_str_mv | AT williamjturbitt dietinducedobesityimpairsoutcomesandinducesmultifactorialdeficienciesineffectortcellresponsesfollowingantictla4combinatorialimmunotherapyinrenaltumorbearingmice AT shannonkboi dietinducedobesityimpairsoutcomesandinducesmultifactorialdeficienciesineffectortcellresponsesfollowingantictla4combinatorialimmunotherapyinrenaltumorbearingmice AT justintgibson dietinducedobesityimpairsoutcomesandinducesmultifactorialdeficienciesineffectortcellresponsesfollowingantictla4combinatorialimmunotherapyinrenaltumorbearingmice AT rachaelmorlandella dietinducedobesityimpairsoutcomesandinducesmultifactorialdeficienciesineffectortcellresponsesfollowingantictla4combinatorialimmunotherapyinrenaltumorbearingmice AT lyseanorian dietinducedobesityimpairsoutcomesandinducesmultifactorialdeficienciesineffectortcellresponsesfollowingantictla4combinatorialimmunotherapyinrenaltumorbearingmice |