Journal Article
. 2020 Jul; 182(3):655-671.e22.
doi: 10.1016/j.cell.2020.06.001.

Molecular Pathways of Colon Inflammation Induced by Cancer Immunotherapy

Adrienne M Luoma 1 Shengbao Suo 2 Hannah L Williams 3 Tatyana Sharova 4 Keri Sullivan 5 Michael Manos 6 Peter Bowling 6 F Stephen Hodi 6 Osama Rahma 7 Ryan J Sullivan 8 Genevieve M Boland 4 Jonathan A Nowak 9 Stephanie K Dougan 1 Michael Dougan 10 Guo-Cheng Yuan 2 Kai W Wucherpfennig 11 
  • PMID: 32603654
  •     62 References
  •     58 citations


Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.

Keywords: CTLA-4; IFNγ; PD-1; TNFα; Trm; cancer; checkpoint blockade; cytotoxic T cells; immune-related adverse events; inflammatory cytokines; irAEs; tissue-resident memory T cells.

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Marie Siwicki, Nicolas A Gort-Freitas, +33 authors, Mikael J Pittet.
Sci Immunol, 2021 Jul 04; 6(61). PMID: 34215680    Free PMC article.
Type I interferon transcriptional network regulates expression of coinhibitory receptors in human T cells.
Tomokazu S Sumida, Shai Dulberg, +9 authors, David A Hafler.
Nat Immunol, 2022 Mar 19; 23(4). PMID: 35301508    Free PMC article.
Single-cell transcriptomic analysis of human colonic macrophages reveals niche-specific subsets.
Diana Domanska, Umair Majid, +5 authors, Frode L Jahnsen.
J Exp Med, 2022 Feb 10; 219(3). PMID: 35139155    Free PMC article.
Integrative analysis of gut microbiome and host transcriptomes reveals associations between treatment outcomes and immunotherapy-induced colitis.
Toshiharu Sakurai, Marco A De Velasco, +9 authors, Masatoshi Kudo.
Mol Oncol, 2021 Jul 17; 16(7). PMID: 34270845    Free PMC article.
Evaluation of the TCR Repertoire as a Predictive and Prognostic Biomarker in Cancer: Diversity or Clonality?
Andrea Aran, Laia Garrigós, +2 authors, Mercè Martí.
Cancers (Basel), 2022 Apr 13; 14(7). PMID: 35406543    Free PMC article.
Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events.
Remo Poto, Teresa Troiani, +4 authors, Gilda Varricchi.
Front Immunol, 2022 Apr 19; 13. PMID: 35432346    Free PMC article.
The Genomic Profile Associated with Risk of Severe Forms of COVID-19 in Amazonian Native American Populations.
Lucas Favacho Pastana, Thays Amâncio Silva, +19 authors, Ney Pereira Carneiro Dos Santos.
J Pers Med, 2022 Apr 24; 12(4). PMID: 35455670    Free PMC article.
Distinct molecular and immune hallmarks of inflammatory arthritis induced by immune checkpoint inhibitors for cancer therapy.
Sang T Kim, Yanshuo Chu, +35 authors, Roza Nurieva.
Nat Commun, 2022 Apr 14; 13(1). PMID: 35413951    Free PMC article.
Exploring the Mechanisms Underlying the Cardiotoxic Effects of Immune Checkpoint Inhibitor Therapies.
Daniel Ronen, Aseel Bsoul, +4 authors, Rabea Asleh.
Vaccines (Basel), 2022 Apr 24; 10(4). PMID: 35455289    Free PMC article.
AXL targeting restores PD-1 blockade sensitivity of STK11/LKB1 mutant NSCLC through expansion of TCF1+ CD8 T cells.
Huiyu Li, Zhida Liu, +30 authors, Rolf A Brekken.
Cell Rep Med, 2022 May 03; 3(3). PMID: 35492873    Free PMC article.
Targeting HIF-1α abrogates PD-L1-mediated immune evasion in tumor microenvironment but promotes tolerance in normal tissues.
Christopher M Bailey, Yan Liu, +5 authors, Yin Wang.
J Clin Invest, 2022 Mar 04; 132(9). PMID: 35239514    Free PMC article.
Tissue-resident memory T cells in gastrointestinal cancer immunology and immunotherapy: ready for prime time?
Syrine Abdeljaoued, Sara Arfa, +6 authors, Christophe Borg.
J Immunother Cancer, 2022 Apr 27; 10(4). PMID: 35470231    Free PMC article.
Treatment of patients with cancer using PD‑1/PD‑L1 antibodies: Adverse effects and management strategies (Review).
Guangshun Sun, Hanyuan Liu, +9 authors, Guoqiang Shao.
Int J Oncol, 2022 Apr 30; 60(6). PMID: 35485291    Free PMC article.
Extricating human tumour immune alterations from tissue inflammation.
Florian Mair, Jami R Erickson, +9 authors, Martin Prlic.
Nature, 2022 May 12; 605(7911). PMID: 35545675