GITR and TIGIT Immunotherapy Provokes Divergent Multi-cellular Responses in the Tumor Microenvironment of Gastrointestinal Cancers

Overview

Journal bioRxiv

Date 2023 Mar 30

PMID 36993756

Authors

Anuja Sathe

Carlos Ayala

Xiangqi Bai

Susan M Grimes

Byrne Lee

Cindy Kin

Andrew Shelton

George Poultsides

Hanlee P Ji

Affiliations

Soon will be listed here.

Abstract

Understanding the cellular mechanisms of novel immunotherapy agents in the human tumor microenvironment () is critical to their clinical success. We examined GITR and TIGIT immunotherapy in gastric and colon cancer patients using slice tumor slice cultures derived from cancer surgical resections. This primary culture system maintains the original TME in a near-native state. We applied paired single-cell RNA and TCR sequencing to identify cell type specific transcriptional reprogramming. The GITR agonist was limited to increasing effector gene expression only in cytotoxic CD8 T cells. The TIGIT antagonist increased TCR signaling and activated both cytotoxic and dysfunctional CD8 T cells, including clonotypes indicative of potential tumor antigen reactivity. The TIGIT antagonist also activated T follicular helper-like cells and dendritic cells, and reduced markers of immunosuppression in regulatory T cells. Overall, we identified cellular mechanisms of action of these two immunotherapy targets in the patients' TME.

References

Aran D, Looney A, Liu L, Wu E, Fong V, Hsu A . Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat Immunol. 2019; 20(2):163-172. PMC: 6340744. DOI: 10.1038/s41590-018-0276-y. View

Nocentini G, Riccardi C . GITR: a modulator of immune response and inflammation. Adv Exp Med Biol. 2009; 647:156-73. DOI: 10.1007/978-0-387-89520-8_11. View

Voabil P, de Bruijn M, Roelofsen L, Hendriks S, Brokamp S, van den Braber M . An ex vivo tumor fragment platform to dissect response to PD-1 blockade in cancer. Nat Med. 2021; 27(7):1250-1261. DOI: 10.1038/s41591-021-01398-3. View

Jiang X, Seo Y, Sullivan K, Pillarisetty V . Establishment of Slice Cultures as a Tool to Study the Cancer Immune Microenvironment. Methods Mol Biol. 2018; 1884:283-295. DOI: 10.1007/978-1-4939-8885-3_20. View

Kenerson H, Sullivan K, Labadie K, Pillarisetty V, Yeung R . Protocol for tissue slice cultures from human solid tumors to study therapeutic response. STAR Protoc. 2021; 2(2):100574. PMC: 8184656. DOI: 10.1016/j.xpro.2021.100574. View

Liu B, Zhang Y, Wang D, Hu X, Zhang Z . Single-cell meta-analyses reveal responses of tumor-reactive CXCL13 T cells to immune-checkpoint blockade. Nat Cancer. 2022; 3(9):1123-1136. DOI: 10.1038/s43018-022-00433-7. View

Togashi Y, Shitara K, Nishikawa H . Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol. 2019; 16(6):356-371. DOI: 10.1038/s41571-019-0175-7. View

Subramanian A, Tamayo P, Mootha V, Mukherjee S, Ebert B, Gillette M . Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005; 102(43):15545-50. PMC: 1239896. DOI: 10.1073/pnas.0506580102. View

Nakhoda S, Olszanski A . Addressing Recent Failures in Immuno-Oncology Trials to Guide Novel Immunotherapeutic Treatment Strategies. Pharmaceut Med. 2020; 34(2):83-91. PMC: 8864519. DOI: 10.1007/s40290-020-00326-z. View

10.

Zimmerman K, Espeland M, Langefeld C . A practical solution to pseudoreplication bias in single-cell studies. Nat Commun. 2021; 12(1):738. PMC: 7854630. DOI: 10.1038/s41467-021-21038-1. View

11.

Niu J, Maurice-Dror C, Lee D, Kim D, Nagrial A, Voskoboynik M . First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer. Ann Oncol. 2021; 33(2):169-180. DOI: 10.1016/j.annonc.2021.11.002. View

12.

Piha-Paul S, Geva R, Tan T, Lim D, Hierro C, Doi T . First-in-human phase I/Ib open-label dose-escalation study of GWN323 (anti-GITR) as a single agent and in combination with spartalizumab (anti-PD-1) in patients with advanced solid tumors and lymphomas. J Immunother Cancer. 2021; 9(8). PMC: 8365809. DOI: 10.1136/jitc-2021-002863. View

13.

Liu B, Hu X, Feng K, Gao R, Xue Z, Zhang S . Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer. Nat Cancer. 2022; 3(1):108-121. DOI: 10.1038/s43018-021-00292-8. View

14.

Tigue N, Bamber L, Andrews J, Ireland S, Hair J, Carter E . MEDI1873, a potent, stabilized hexameric agonist of human GITR with regulatory T-cell targeting potential. Oncoimmunology. 2017; 6(3):e1280645. PMC: 5384396. DOI: 10.1080/2162402X.2017.1280645. View

15.

Li H, van der Leun A, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi A . Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell. 2019; 176(4):775-789.e18. PMC: 7253294. DOI: 10.1016/j.cell.2018.11.043. View

16.

Qu Y, Taylor J, Bose A, Storkus W . Therapeutic effectiveness of intratumorally delivered dendritic cells engineered to express the pro-inflammatory cytokine, interleukin (IL)-32. Cancer Gene Ther. 2011; 18(9):663-73. PMC: 3348582. DOI: 10.1038/cgt.2011.37. View

17.

Hafemeister C, Satija R . Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 2019; 20(1):296. PMC: 6927181. DOI: 10.1186/s13059-019-1874-1. View

18.

Manieri N, Chiang E, Grogan J . TIGIT: A Key Inhibitor of the Cancer Immunity Cycle. Trends Immunol. 2016; 38(1):20-28. DOI: 10.1016/j.it.2016.10.002. View

19.

Sathe A, Grimes S, Lau B, Chen J, Suarez C, Huang R . Single-Cell Genomic Characterization Reveals the Cellular Reprogramming of the Gastric Tumor Microenvironment. Clin Cancer Res. 2020; 26(11):2640-2653. PMC: 7269843. DOI: 10.1158/1078-0432.CCR-19-3231. View

20.

Korsunsky I, Millard N, Fan J, Slowikowski K, Zhang F, Wei K . Fast, sensitive and accurate integration of single-cell data with Harmony. Nat Methods. 2019; 16(12):1289-1296. PMC: 6884693. DOI: 10.1038/s41592-019-0619-0. View