T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation.

Details

• Alternative Title:
  Cancer Immunology Research, 2025, v. 13, no. 2: T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation.
• Journal Article:
  Cancer Immunology Research
• Personal Author:
  Cho, Nam Woo ; Guldberg, Sophia M. ; Nabet, Barzin Y. ; Yu, Jie Zeng ; Kim, Eun Ji ; Hiam-Galvez, Kamir J. ; Yee, Jacqueline L. ; DeBarge, Rachel ; Tenvooren, Iliana ; Ashitey, Naa Asheley ; Lynce, Filipa ; Dillon, Deborah A. ; Rosenbluth, Jennifer M. ; Spitzer, Matthew H.
• Description:
  Resistance to immune checkpoint inhibitors (ICI) is common, even in tumors with T-cell infiltration. We thus investigated consequences of ICI-induced T-cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL1 receptor 1, enabling a synergistic response to IL1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T-cell activity can drive resistance in tumors responsive to IL1 and TNFα, with important therapeutic implications.
• Content Notes:
  Author manuscript
• Subjects:
  • Immune Checkpoint Inhibitors
  • Tumor Necrosis Factor-alpha
  • Humans
  • Drug Resistance, Neoplasm
  • Animals
  • Interleukin-1
  • Mice
  • T-Lymphocytes
  • Inflammation
  • Tumor Microenvironment
  More +
• Keywords:
  • Cancer Immunotherapy
  • Immune Checkpoint Inhibitors
  • Immunotherapy Resistance
  • MDSCs
  • IL-1 Receptor Signaling in Cancer
  • TNFα Signaling
  • NF-kB Signaling
  • T cell-mediated Immunosuppression
• Source:
  Cancer Immunology Research, 2025, v. 13, no. 2
• DOI:
  https://doi.org/10.1158/2326-6066.CIR-24-0416
• ISSN:
  2326-6066 ; 2326-6074
• Pubmed ID:
  39404741
• Pubmed Central ID:
  PMC11790381
• Document Type:
  Text
• Funding:
  T32 AI007334/AI/NIAID NIH HHSUnited States/ ; 1P50CA168504/National Cancer Institute (NCI)/ ; R01 DE032033/DE/NIDCR NIH HHSUnited States/ ; ImmunoX Computational Biology Initiative/University of California, San Francisco (UCSF)/ ; P50 CA168504/CA/NCI NIH HHSUnited States/ ; Parker Fellow/Parker Institute for Cancer Immunotherapy (PICI)/ ; T32GM1365471/National Institute of General Medical Sciences (NIGMS)/ ; 20-20-01-SPIT/American Association for Cancer Research (AACR)/ ; Stanford Propel Postdoctoral Scholarship/Stanford University (SU)/ ; T32 GM136547/GM/NIGMS NIH HHSUnited States/ ; DP5 OD023056/CD/ODCDC CDC HHSUnited States/ ; T32 5T32AI007334-33/National Institute of Allergy and Infectious Diseases (NIAID)/ ; F31 CA265128/CA/NCI NIH HHSUnited States/ ; GRFP fellowship/National Science Foundation Graduate Research Fellowship Program (GRFP)/ ; DP5 OD023056/OD/NIH HHSUnited States/ ; Clinician Scientist Development Grant ASTRO-CSDG-23-1036400-01-IBCD/American Cancer Society (ACS)/ ; F31 CA271748/CA/NCI NIH HHSUnited States/ ; S10 OD018040/CD/ODCDC CDC HHSUnited States/ ; S10 OD018040/OD/NIH HHSUnited States/ ; CRI4437/Cancer Research Institute (CRI)/ ; RSG-22-141-01-IBCD/American Cancer Society (ACS)/ ; BC220499/U.S. Army Medical Research Acquisition Activity (USAMRAA)/ ; R01 CA290027/CA/NCI NIH HHSUnited States/ ; F31CA271748/National Cancer Institute (NCI)/ ; UCSF Prostate Cancer Program Pilot/University of California, San Francisco (UCSF)/ ; Investigator support/Chan Zuckerberg Biohub/
• Genre:
  Journal Article
• Pages in Document:
  229-244 (36 pdf pages)
• Volume:
  13
• Issue:
  2
• Download URL:
  https://stacks.cdc.gov/view/cdc/261981/cdc_261981_DS1.pdf
• File Type:
  [PDF - 2.91 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:a8c8f602a5b1c7d93bba3a629ee94d8dafafd99915d0c18f8696ef56a299f258e3397feff72d8ac867c9c462156173755cf8b919a1e50ac701a1f16af28a9213