Basic Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Oncol. Apr 24, 2021; 12(4): 238-248
Published online Apr 24, 2021. doi: 10.5306/wjco.v12.i4.238
Cytotoxic CD8+ T cells and tissue resident memory cells in colorectal cancer based on microsatellite instability and BRAF status
James Wei Tatt Toh, Angela L Ferguson, Kevin J Spring, Hema Mahajan, Umaimainthan Palendira
James Wei Tatt Toh, Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Westmead Clinical School, The University of Sydney, Ingham Institute for Applied Medical Research, Westmead 2145, NSW, Australia
Angela L Ferguson, Department of Infectious Diseases and Immunology, School of Medical Sciences, Faculty of Medicine and Health, Human Viral & Cancer Immunology, Centenary Institute, Charles Perkin Centre, The University of Sydney, Sydney 2000, NSW, Australia
Kevin J Spring, Medical Oncology Group, Ingham Institute for Applied Medical Research, Liverpool Hospital, Liverpool Clinical School, University of Western Sydney, South Western Clinical School UNSW, Liverpool 2170, NSW, Australia
Hema Mahajan, Department of Anatomical Pathology, ICPMR, Westmead Hospital, Westmead 2145, NSW, Australia
Umaimainthan Palendira, Department of Immunology and Infectious Diseases, School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney 2000, NSW, Australia
Author contributions: Toh JWT and Ferguson A are co-first authors; Toh JWT, Ferguson A and Palendira U conceptualized and designed the study experimental and analytical methods; Toh JWT wrote the manuscript; Palendira U and Spring KJ supervised the project; Toh JWT, Ferguson A, Palendira U, Spring KJ and Mahajan H were involved in critical revisions of the manuscript.
Institutional review board statement: This study was reviewed and approved by the Executive Ethical Review Panel of the Sydney Local Health District - CRGH Human Research Ethics Committee.
Conflict-of-interest statement: The authors declare no conflicts of interest and have no financial disclosures.
Data sharing statement: Data supporting the results in the paper available on request.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: James Wei Tatt Toh, BSc, MBBS, Senior Lecturer, Surgeon, Division of Surgery and Anaesthesia, Department of Colorectal Surgery, Westmead Hospital, Cnr Hawkesbury and Darcy Rd, Westmead 2145, NSW, Australia. james.toh@sydney.edu.au
Received: January 14, 2021
Peer-review started: January 14, 2021
First decision: February 15, 2021
Revised: March 14, 2021
Accepted: April 5, 2021
Article in press: April 5, 2021
Published online: April 24, 2021
Processing time: 96 Days and 12.5 Hours
Abstract
BACKGROUND

Recent studies in non-colorectal malignancy have associated T resident memory (TRM) cells with improved patient survival. It is unknown if TRM plays a role in colorectal cancer (CRC).

AIM

To examine the potential role of TRM cells in providing immunogenicity in CRC stratified by microsatellite instability (MSI) and BRAF status.

METHODS

Patients with known MSI and BRAF mutation status were eligible for inclusion in this study. CRC tumour sections stained with haematoxylin and eosin were microscopically reviewed and the images scanned prior to assessment for location of invading edge and core of tumour. Sequential sections were prepared for quantitative multiplex immunohistochemistry (IHC) staining. Opal Multiplex IHC staining was performed with appropriate positive and negative controls and imaged using a standard fluorescent microscope fitted with a spectral scanning camera (Mantra) in conjunction with Mantra snap software. Images were unmixed and annotated in inForm 2.2.0. Statistical analysis was performed using Graphpad Prism Version 7 and Stata Version 15.

RESULTS

Seventy-two patients with known MSI and BRAF status were included in the study. All patients were assessed for MSI by IHC and high resolution capillary electrophoresis testing and 44 of these patients successfully underwent quantitative multiplex IHC staining. Overall, there was a statistically significant increase in CD8+ TRM cells in the MSI (BRAF mutant and wild type) group over the microsatellite stable (MSS) group. There was a statistically significant difference in CD8+ TRM between high level MSI (MSI-H):BRAF mutant [22.57, 95% confidence interval (CI): 14.31-30.84] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0076 andMSI-H:BRAF wild type [16.18 (95%CI: 10.44-21.93)] vs MSS [8.031 (95%CI: 4.698-11.36)], P = 0.0279. There was no statistically significant difference in CD8 T cells (both CD8+CD103- and CD8+CD103+TRM) between MSI-H: BRAF mutant and wild type CRC.

CONCLUSION

This study has shown that CD8+ TRM are found in greater abundance in MSI-H CRC, both BRAF mutant and MSI-H:BRAF wild type, when compared with their MSS counterpart. CD8+ TRM may play a role in the immunogenicity in MSI-H CRC (BRAF mutant and BRAF wild type). Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC.

Keywords: Tissue resident memory cells; Resident memory T cells; Colorectal cancer; Microsatellite instability; BRAF; DNA mismatch repair; Immunotherapy; Prognosis

Core Tip: Prior to this study, whether T resident memory (TRM) cells exist in colorectal cancer (CRC) was poorly understood. This study has identified and characterize TRM cells within human CRC. CD8+ TRM cells are found in greater abundance in both high microsatellite instability (MSI-H) BRAF mutant and MSI-H:BRAF wild type CRC when compared with their microsatellite stable counterpart. CD8+ TRM may play a role in the immunogenicity in both BRAF mutant and BRAF wild type MSI-H CRC. Further studies should focus on the potential immunogenic qualities of TRM cells and investigate potential immunotherapeutic approaches to improve treatment and survival associated with CRC based on TRM.