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Review
. 2022 Sep 27:13:1016646.
doi: 10.3389/fimmu.2022.1016646. eCollection 2022.

Mechanism and strategies of immunotherapy resistance in colorectal cancer

Jiqi Shan  1 , Dong Han  1 , Chunyi Shen  1 , Qingyang Lei  1 , Yi Zhang  1   2   3
Affiliations
Review

Mechanism and strategies of immunotherapy resistance in colorectal cancer

Jiqi Shan et al. Front Immunol. .

Abstract

Colorectal cancer (CRC) is the third most common cancer in the world. Although there are standard treatment options for CRC, most patients respond poorly to these treatments. Immunotherapies have gradually emerged due to the increasing awareness and understanding of tumor immunity, exhibiting good therapeutic efficacy in various cancers. Immunotherapies include cytokines, immune checkpoint inhibitors (ICIs), and adoptive cell therapies. In particular, ICIs, which are antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or its ligand PD-L1, have been successfully applied clinically for solid tumors, relieving the inhibitory effect of the tumor microenvironment on T cells. However, only a minority of patients with cancer achieve a durable clinical response during immunotherapy. Several factors restrict the efficacy of immunotherapy, leading to the development of drug resistance. In this review, we aimed to discuss the current status of immunotherapy for CRC and elaborate on the mechanisms that mediate resistance to immunotherapy and other potential therapeutic strategies.

Keywords: colorectal cancer; drug resistance; immune checkpoint inhibitors; immunotherapy; potential therapeutic strategies.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Two outcomes of immunotherapy in dMMR–MSI-H and pMMR–MSI-L CRC. Compared with pMMR–MSI-L, patients with dMMR–MSI-H experience better tumor reduction after treatment with immune checkpoint inhibitors (ICIs). Many functional tumor infiltrating lymphocytes (TILs) release a large number of cytokines such as IFN-γ and granzyme B in the dMMR–MSI-H tumor microenvironment (TME). However, the TME of pMMR–MSI-L CRC contains fewer functional TILs and more immunosuppressive cells, such as Tregs, MDSCs, and TAMs, which inhibit TIL function.
Figure 2
Figure 2
Mechanisms associated with immunotherapy resistance. The limited effectiveness of immunotherapy is primarily due to various mechanisms of immunotherapy resistance. In the heterogeneous tumor microenvironment, cells such as Tregs, MDSCs, and TAMs, combined with tumor-released immunosuppressive cytokines, induce tumor infiltrating lymphocytes (TILs) exhaustion. In the TME, tumor cells have a greater ability to compete for nutrients, such as glucose, glutamine, and tryptophan, which are necessary for proper cellular function. Meanwhile, tumor cells release lactate, kynurenine, and Oxidized low density lipoprotein (oxLDLs), which are harmful to TILs. In CRC, intestinal microbiota such as P. anaerobius and enterotoxigenic B ragilis induce tumor cells to release CXCL1, CXCL2, and CXCL5 and recruit immunosuppressive cells. Before identifying and killing TILs, tumor cells activate the lysosomal degradation pathway of MHC class 1 to escape T cell killing. The switching/sucrose non-fermentable (SWI/SNF) complex has been identified as a tumor suppressor gene in CRC; AT-Rich Interactive Domain-containing protein 1A (ARID1A) is the most frequent target of SWI/SNF mutations. However, ARID1A mutations was found correlated with markedly higher level of immune infiltrates in colon cancer. Gene and signal pathway mutations, such as those in WNT, RAS, BRAF, MEK, ERK, PI3KCA, and PTEN, were reported to be associated with immunotherapy resistance.
Figure 3
Figure 3
Strategies for overcoming immunotherapy resistance in CRC. The resistance leads to an ineffective immunotherapy and tumor progression. Four distinct strategies against immunotherapy resistance are listed: promoting tumor antigen presentation, regulating tumor immunosupprssive microenvironment, manipulating intestinal microbiota and others including combination therapy etc. Inhibiting MHC degradation and boosting dendritic cell proliferation could elevate tumor antigen presentation; Targeting immunosuppressive cells, cytokines in Tumor microenvironment (TME) and nutrient transporters help CD8+T escape the inhibition of TME. In addition, gut microbiota and its metabolite are widely proven to participate in tumor growth and immune response. Consistantly, fecal microbiota transplantation makes patients sensitive to immunotherapy. Other strategies for overcoming immunotherapy resistance, such as the administration of chemoimmunotherapy, immune adjuvant, oncolytic vaccinia virus can also improve the sensitivity of immunotherapy in CRC.
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