Letter to the Editor Open Access
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2022; 14(6): 1213-1215
Published online Jun 15, 2022. doi: 10.4251/wjgo.v14.i6.1213
Insight on BRAFV600E mutated colorectal cancer immune microenvironment
Hassan Mohammed Abushukair, Faculty of Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
Sara Mu'amar Zaitoun, Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan
Anwaar Saeed, Department of Medicine, Division of Medical Oncology, The University of Kansas Cancer Center, Kansas City, KS 66205, United States
ORCID number: Hassan Mohammed Abushukair (0000-0002-0068-5201); Sara Mu'amar Zaitoun (0000-0002-0317-612X); Anwaar Saeed (0000-0001-8024-9401).
Author contributions: Abushukair HM and Zaitoun SM drafted the manuscript and contributed to conceptualization; Saeed A contributed to conceptualization of core concepts and critically revised the draft.
Conflict-of-interest statement: Saeed A reports research grants from AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, KAHR Medical, and Incyte, and advisory board fees from AstraZeneca, Bristol Myers Squibb, Merck, Exelixis, and Pfizer. The other authors report no conflicts of interest.
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: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Anwaar Saeed, MD, Department of Medicine, Division of Medical Oncology, The University of Kansas Cancer Center, 2330 Shawnee Mission Pkwy, Suite 210, Kansas City, KS 66205, United States. asaeed@kumc.edu
Received: January 27, 2022
Peer-review started: January 27, 2022
First decision: April 17, 2022
Revised: May 4, 2022
Accepted: May 21, 2022
Article in press: May 21, 2022
Published online: June 15, 2022


Colorectal cancer (CRC) is the second deadliest malignancy for both sexes. The BRAFV600E mutation, one of the most common driver mutations in CRC, is known for its poor prognosis due to the increased risk of metastasis. The effect of the BRAFV600E mutation on the tumor microenvironment was the topic of the study reported in World Journal of Gastrointestinal Oncology, with special focus on immune status. The authors presented insightful findings that were exclusively based on macrophage polarity and cytokine levels, without investigating other relevant immune elements. A more comprehensive look into the dynamic immune activity of cancer environments will warrant more meaningful practical findings. In this letter, we discuss other significant immune factors and their possible implications on the tumor microenvironment of BRAF-mutated CRC.

Key Words: Colorectal cancer, BRAFV600E, Tumor microenvironment, Microsatellite instability, Macrophages, Immune checkpoint proteins

Core Tip: The immune landscape of the tumor microenvironment is a crucial indicator of the proliferative and invasive activity of the tumor cells and serves as a predictor of response to targeted immunotherapeutic modalities. BRAFV600E is one of the most common driver mutations in colorectal cancer thought to have a unique impact on the tumor immune microenvironment. It is unknown whether this impact is of a suppressive or activating nature. Future studies on larger samples, considering a wider array of immune elements, such as the infiltration of relevant immune cells as well as immune checkpoints’ expression, are needed.


We read the interesting study by Zhi et al[1] on the immune status of BRAFV600E-mutated colorectal cancer (CRC), titled “BRAFV600E mutant colorectal cancer cells mediate local immunosuppressive microenvironment through exosomal long noncoding RNAs”, in which they utilized patient tissue samples, CRC cell lines as well as in silico analysis to study correlations between the BRAFV600E mutation and changes in the local immune microenvironment of CRC. The authors reported an immunosuppressive microenvironment induced by exosomal long noncoding RNAs in BRAFV600E mutant CRC as well as higher angiogenic and lymphangiogenic activity compared to wild-type CRC.

We would like to point out the complementary findings to this study from previous work that has alluded to other parts of the immune landscape of the tumor microenvironment of BRAFV600E CRC. From this study, Zhi et al[1] reported a higher level of M2 macrophages in BRAFV600E-mutated patients compared to the wild-type, with no difference in M1 macrophages levels. Yet, the sample number from which these results were obtained was relatively small (BRAFV600E mutation: 10; BRAF wild-type: 20), and this translated to high standard deviations in the M2 counts in both samples. In a recent study by Cen et al[2], which used a larger sample (mutated patients: 110, wild-type patients: 798) from the Cancer Genomic Atlas and the Gene Expression Omnibus databases, the authors reported a higher immune cell infiltration and lower tumor purity. Specifically, a higher proportion of CD8+ T cells, M1 macrophages as well as neutrophils were found in BRAFV600E-mutated CRC patients, whereas no difference was found in M2 macrophage levels. Furthermore, according to the consensus molecular subtypes’ classification, which provides the most comprehensive description of CRC heterogeneity at the gene expression level, BRAFV600E mutation is associated with consensus molecular subtype 1, which correlates with high immune infiltration and immune-response pathway activity[3].

Interestingly, subtypes of BRAFV600E based on expression patterns in CRC have been further identified. There are two subtypes regardless of microsatellite instability, PI3K mutation status, sex and sidedness: BM1 and BM2[4]. Differences between those subtypes exist, including the prognosis (BM1 was found to have a poorer prognosis than BM2) and the immune status. BM1 has an overall stronger immune profile, emphasized by the activation of pathways like IL2/STAT5, tumor necrosis factor-α signaling via nuclear factor kappa B, IL6/JAK/STAT3 and allograft rejection[4]. Taking these subtypes into consideration will reveal a deeper understanding of the tumor immune microenvironment in BRAF-mutated CRC patients.

The immune status of the tumor microenvironment is a multilayered complex subject that leads to crucial implications regarding tumor cell immune evasion, therapeutic response or distant invasion tendency. Therefore, we feel that limiting the immune landscape to the levels of tumor-associated macrophages (M1/2) and cancer-associated fibroblasts, as in the study by Zhi et al[1], would not reflect the whole story. This is particularly due to the fact that other key immune components, such as CD8+ and CD4+ T cells, neutrophils, myeloid-derived suppressor cells and regulatory T cells, were not investigated. Of note, higher levels of cytotoxic CD8+ T cells could possibly be neutralized in the tumor microenvironment by immune checkpoints, such as programmed death protein and its ligand or cytotoxic T lymphocyte-associated protein 4[5]. In addition, microsatellite status is of paramount importance in this context, since a higher abundance of CD8+ T cells, activated natural killer cells and M1 macrophages, and upregulated immune checkpoints were identified in microsatellite instability compared to microsatellite-stable CRC[6]. Hence, future investigations including a wider array of immune components, taking into consideration significant genomic features (microsatellite instability and tumor mutational burden), will likely shed light on more reflective findings into the tumor immune status.

In conclusion, the authors presented compelling findings that provide a new perspective on BRAFV600E-mutated CRC immune microenvironment by discussing a proposed mechanism for inducing an immunosuppressed state through the release of exosomal long noncoding RNAs. Future studies targeting this topic should take into consideration the entire spectrum of the dynamic immune activity in the tumor microenvironment, covering relevant immune cells, immune checkpoints and molecular aberrations. Such comprehensive studies will provide insight for promising therapeutic opportunities for this subset of CRC patients.


Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Corresponding Author's Membership in Professional Societies: American Society of Clinical Oncology.

Specialty type: Oncology

Country/Territory of origin: United States

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): B, B

Grade C (Good): 0

Grade D (Fair): 0

Grade E (Poor): 0

P-Reviewer: Liu Z, China; Xiao T, China A-Editor: Lin FY, China S-Editor: Fan JR L-Editor: A P-Editor: Fan JR

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