T Cells in Colorectal Cancer - Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment

Sep 24, 2026

Therapeutic options for metastatic colorectal cancer remain limited, with poor survival despite combined chemotherapy and targeted drugs. Checkpoint inhibitor blockade has changed treatment in other cancers, yet in colorectal cancer it largely benefits only microsatellite instability-high or mismatch repair-deficient tumors. Most sporadic CRCs are microsatellite-stable and show low immune-cell infiltration, leading to no clinical benefit. Immunotherapy requires T cell presence in the tumor microenvironment, where T-cell subsets are heterogeneous and can be exhausted, dysfunctional, or checkpoint-high; this review discusses their roles and CAR-T potential.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages35

Reading Time1 h 28 min

AccessFree to download

Abstract

1. Introduction

1.1. Immune Cell Infiltration into the Consensus Molecular CRC Subtypes

Review T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment Ziwen Zheng 1, Thomas Wieder 2, Bernhard Mauerer 1,3,4, Luisa Schäfer 1, Rebecca Kesselring 1,3,4,† and Heidi Braumüller 1, *,† Citation: Zheng, Z.; Wieder, T.; Mauerer, B.; Schäfer, L.; Kesselring, R.; Braumüller, H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsetsin the Tumor Microenvironment. Int. J. Mol. Sci. 2023, 24, 11673. [https://](https://)[ ](https://)[doi.org/10.3390/ijms241411673](doi.org/10.3390/ijms241411673) Academic Editor: Carmine Stolﬁ Received: 16 June 2023 Revised: 17 July 2023 Accepted: 18 July 2023 Published: 19 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department of General and Visceral Surgery, Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; [ziwen.zheng@uniklinik-freiburg.de](ziwen.zheng@uniklinik-freiburg.de) (Z.Z.); [bernhard.mauerer@uniklinik-freiburg.de](bernhard.mauerer@uniklinik-freiburg.de) (B.M.); [luisa.schaefer@uniklinik-freiburg.de](luisa.schaefer@uniklinik-freiburg.de) (L.S.); [rebecca.kesselring@uniklinik-freiburg.de](rebecca.kesselring@uniklinik-freiburg.de) (R.K.) 2 Department of Vegetative and Clinical Physiology, Institute of Physiology, Eberhard Karls University Tübingen, 72074 Tübingen, Germany; thomas.wieder@uni-tuebingen.de 3 German Cancer Consortium (DKTK) Partner Site Freiburg, 79106 Freiburg, Germany 4 German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany * Correspondence: heidi.braumueller@uniklinik-freiburg.de † These authors contributed equally to this work. Abstract: Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25–30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deﬁcient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of inﬁltrating immune cells, in which immunotherapy has no clinical beneﬁt so far. Immunotherapy with checkpoint inhibitors requires the presence of inﬁltrating T cells into the tumor microenvironment (TME) . This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore—a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or protumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a 􀀍􀀎 T cell receptor can overcome the limitations of the conventional CD8+ T cells with an 􀀋􀀌T cell receptor. 􀀍􀀎 T cells recognize antigens in an MHC-indep

FAQs

Why does checkpoint inhibitor therapy work poorly in most colorectal cancer patients?

In most sporadic colorectal cancers, tumors are microsatellite-stable with low infiltration of immune cells, so checkpoint blockade has limited effect. Only MSI-H or dMMR tumors generally show meaningful benefit.

What role do T cells play in the tumor microenvironment for immunotherapy?

Checkpoint inhibitors require infiltrating T cells in the tumor microenvironment. T cells are key effector cells, and the immunoscore reflects their prognostic importance in colorectal cancer.

How can the limitations of conventional CD8+ T cells be addressed?

Even CD8+ T cells can become exhausted, hyporesponsive, or dysfunctional and express checkpoint molecules. Unconventional T cell subsets with a distinct T cell receptor can recognize antigens in an MHC-independent manner and may help bridge innate and adaptive immunity; the review also considers overcoming T cell exclusion in “cold” tumors and discusses CAR-T possibilities.

Sep 24, 2026

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