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Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.

Publication ,  Journal Article
Hwang, B-J; Tsao, L-C; Acharya, CR; Trotter, T; Agarwal, P; Wei, J; Wang, T; Yang, X-Y; Lei, G; Osada, T; Lyerly, HK; Morse, MA; Hartman, ZC
Published in: J Immunother Cancer
March 2022

BACKGROUND: The majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. METHODS: We first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. RESULTS: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. CONCLUSION: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.

Duke Scholars

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Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

March 2022

Volume

10

Issue

3

Location

England

Related Subject Headings

  • Signal Transduction
  • Mice
  • Immunotherapy
  • Immune Checkpoint Inhibitors
  • Humans
  • Colorectal Neoplasms
  • Antiviral Agents
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology
 

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Hwang, B.-J., Tsao, L.-C., Acharya, C. R., Trotter, T., Agarwal, P., Wei, J., … Hartman, Z. C. (2022). Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression. J Immunother Cancer, 10(3). https://doi.org/10.1136/jitc-2021-003721
Hwang, Bin-Jin, Li-Chung Tsao, Chaitanya R. Acharya, Timothy Trotter, Pankaj Agarwal, Junping Wei, Tao Wang, et al. “Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.J Immunother Cancer 10, no. 3 (March 2022). https://doi.org/10.1136/jitc-2021-003721.
Hwang B-J, Tsao L-C, Acharya CR, Trotter T, Agarwal P, Wei J, et al. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression. J Immunother Cancer. 2022 Mar;10(3).
Hwang, Bin-Jin, et al. “Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression.J Immunother Cancer, vol. 10, no. 3, Mar. 2022. Pubmed, doi:10.1136/jitc-2021-003721.
Hwang B-J, Tsao L-C, Acharya CR, Trotter T, Agarwal P, Wei J, Wang T, Yang X-Y, Lei G, Osada T, Lyerly HK, Morse MA, Hartman ZC. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression. J Immunother Cancer. 2022 Mar;10(3).
Journal cover image

Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

March 2022

Volume

10

Issue

3

Location

England

Related Subject Headings

  • Signal Transduction
  • Mice
  • Immunotherapy
  • Immune Checkpoint Inhibitors
  • Humans
  • Colorectal Neoplasms
  • Antiviral Agents
  • Animals
  • 3211 Oncology and carcinogenesis
  • 3204 Immunology