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Muto, S.;  Enta, A.;  Maruya, Y.;  Inomata, S.;  Yamaguchi, H.;  Mine, H.;  Takagi, H.;  Ozaki, Y.;  Watanabe, M.;  Inoue, T.; et al. Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling. Encyclopedia. Available online: https://encyclopedia.pub/entry/40562 (accessed on 12 July 2025).
Muto S,  Enta A,  Maruya Y,  Inomata S,  Yamaguchi H,  Mine H, et al. Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling. Encyclopedia. Available at: https://encyclopedia.pub/entry/40562. Accessed July 12, 2025.
Muto, Satoshi, Akio Enta, Yoshiyuki Maruya, Sho Inomata, Hikaru Yamaguchi, Hayato Mine, Hironori Takagi, Yuki Ozaki, Masayuki Watanabe, Takuya Inoue, et al. "Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling" Encyclopedia, https://encyclopedia.pub/entry/40562 (accessed July 12, 2025).
Muto, S.,  Enta, A.,  Maruya, Y.,  Inomata, S.,  Yamaguchi, H.,  Mine, H.,  Takagi, H.,  Ozaki, Y.,  Watanabe, M.,  Inoue, T.,  Yamaura, T.,  Fukuhara, M.,  Okabe, N.,  Matsumura, Y.,  Hasegawa, T.,  Osugi, J.,  Hoshino, M.,  Higuchi, M.,  Shio, Y., ... Suzuki, H. (2023, January 30). Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling. In Encyclopedia. https://encyclopedia.pub/entry/40562
Muto, Satoshi, et al. "Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling." Encyclopedia. Web. 30 January, 2023.
Overcoming Immune-Checkpoint-Inhibitor Resistance with Wnt/β-Catenin Signaling
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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11010190

Lung cancer is the leading cause of cancer-related deaths worldwide. The standard of care for advanced non-small-cell lung cancer (NSCLC) without driver-gene mutations is a combination of an anti-PD-1/PD-L1 antibody and chemotherapy, or an anti-PD-1/anti-programmed death ligand-1 (PD-L1) antibody and an anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody with or without chemotherapy. Although there were fewer cases of disease progression in the early stages of combination treatment than with anti-PD-1/PD-L1 antibodies alone, only approximately half of the patients had a long-term response. Therefore, it is necessary to elucidate the mechanisms of resistance to immune checkpoint inhibitors. Recent reports of such mechanisms include reduced cancer-cell immunogenicity, loss of major histocompatibility complex, dysfunctional tumor-intrinsic interferon-γ signaling, and oncogenic signaling leading to immunoediting. Among these, the Wnt/β-catenin pathway is a notable potential mechanism of immune escape and resistance to immune checkpoint inhibitors.

immune checkpoint inhibitors tumor Wnt/β-catenin

1. Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, with approximately 1.8 million deaths in 2020 [1]. Up to half of lung-cancer patients, including those undergoing surgical resection, will unfortunately develop disease recurrence [2].
The current standard of care for advanced non-small-cell lung cancer (NSCLC) is molecular-targeted agents, chemotherapy, and immune checkpoint inhibitors. Molecular-targeted agents have improved the outcome of advanced NSCLC cases [3]. However, their indications are limited to patients with specific driver-gene mutations. Therefore, the development of immune checkpoint inhibitors has been promoted. Initially, anti-programmed death-1 (PD-1) antibodies [4][5][6] or anti-programmed death ligand-1 (PD-L1) monotherapy [7][8] was used, but combinations with chemotherapy [9][10][11][12][13] or anti-cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibodies [14][15][16] have improved outcome, and have now been approved for the treatment of advanced NSCLC.
The therapeutic effects of immune checkpoint inhibitors are characterized by an impressive durable response. However, even in NSCLC patients with high PD-L1 expression who would benefit from anti-PD-1 or anti-PD-L1 antibodies, only approximately half of them achieve long-term responses to immune checkpoint inhibitors [9][10][11][12][13][14][15]. There is an urgent need to achieve therapeutic effects in patients who display resistance to immune checkpoint inhibitors. Therefore, it is necessary to elucidate the specific molecular mechanisms associated with resistance to immune checkpoint inhibitors.

2. Combination Therapy with Chemotherapy and Immune Checkpoint Inhibitors

The combination of immune checkpoint inhibitors and chemotherapy can reportedly enhance therapeutic efficacy, especially in NSCLC [9][10][11][12][13]. Cytotoxic chemotherapy can result in immunogenic cell death, promote antigen presentation by dendritic cells [17], and eliminate myeloid-derived suppressor cells (MDSCs) [18] and Tregs [19]. Radiotherapy similarly induces immunogenic cell death, and is expected to enhance the efficacy of immune checkpoint inhibitors, either alone or in combination with chemotherapy [20][21][22]. Chemotherapy and radiotherapy are expected to promote antigen presentation and T-cell recruitment in tumors with active Wnt/β-catenin signaling. There have been no reports examining the effect of chemotherapy combined with immune checkpoint inhibitors in β-catenin-activated cancers. However, the results of chemotherapy combined with immune checkpoint inhibitors in NSCLC suggest that there may be additive but not synergistic effects. This means that although they may inhibit cancer progression or control tumor burden in the short term, they do not seem to increase the proportion of patients who achieve a long-term response to immune checkpoint inhibitors. Comparing the results of clinical trials of pembrolizumab alone with those of pembrolizumab combined with chemotherapy in non-squamous NSCLC patients, the data suggest that the combination with chemotherapy was able to reduce disease progression in the early treatment period, but has made little difference to long-term survival [23][24][25]. Cancers with activated β-catenin signaling are considered “immunologically cold” tumors, and often have low or negative PD-L1 expression [26]. Therefore, the additive effect of chemotherapy is likely to be temporary. Lung cancers with β-catenin-pathway activation have been shown to be resistant to chemotherapy, and patients have a poor prognosis with or without adjuvant chemotherapy [27][28]. Similarly to STK11 genomic aberrations, activation of the β-catenin pathway may be a prognostic factor rather than a predictor of response to combination therapy of immune checkpoint inhibitors and chemotherapy [29]. In a mouse model of melanoma, using an anti-PD-1 antibody plus an anti-CTLA-4 antibody had no effect on tumors with β-catenin activation [30]. The combination of other immune checkpoint inhibitors and molecular targeting-agents would likely be similarly ineffective.
Activation of the β-catenin pathway is frequently observed in hepatocellular carcinoma [31], and is linked to resistance to immunotherapies [32]. However, another report states that the combination of an anti-PD-L1 antibody with an anti-VEGF antibody showed efficacy, regardless of β-catenin-pathway activation [33]. In liver tumors, the tumor microenvironment is highly glycolytic, and Tregs express PD-1 more frequently than effector T cells [34]. Additionally, anti-PD-1 antibodies are ineffective when PD-1 is more highly expressed in Tregs than in effector T cells [35]. These data suggest that the therapeutic strategy of suppressing Tregs with an anti-VEGF antibody in combination with an anti-PD-L1 antibody may be effective in the treatment of hepatocellular carcinoma.

3. Neoadjuvant Treatment Strategies

If it is difficult to treat cancers with activated β-catenin signaling long-term, by combining chemotherapy and immune checkpoint inhibitors, a possible strategy may be performing surgical resection while the lesion is shrinking to some extent. There have been numerous clinical trials of neoadjuvant treatment methods for NSCLC, albeit in the resectable stage rather than for advanced cases. In the CheckMate 816 trial, surgical resection after four courses of nivolumab and chemotherapy resulted in pathological complete response in 24% of stage IB to IIIA resectable-NSCLC patients [36]. Results from the phase 2 NADIM trial have also been published, but the relationship between activation of the β-catenin pathway and survival or pathological response-rates has not been published [37]. For reference, of the 26 patients who achieved a complete pathological response, one patient had disease progression, and this patient had an EGFR mutation. Of the seven patients with major pathological response (≤10% viable tumor cells), one had mutations in STK11 and had disease progression [37]. These findings suggest that even in a resectable neoadjuvant setting, it may be difficult to expect long-term efficacy using a combination-therapy approach with chemotherapy and an immune checkpoint inhibitor, as oncogenic signals can lead to tumor-intrinsic immune evasion. In addition, surgical resection was canceled in five of the forty-six patients who received neoadjuvant therapy in the phase 2 trial, and in 15.6% patients in the nivolumab-plus-chemotherapy group in the phase 3 trial [36][37]. Reasons for cancellation varied, but included those who could not undergo surgery because of disease progression. When neoadjuvant treatment is administered on tumors with active β-catenin signaling, the pathological response rate and percentage of patients who could undergo surgery should be confirmed in the future.

4. Combination Therapy with Inhibitors of Wnt/β-Catenin Signaling and Immune Checkpoint Inhibitors

The simplest way to suppress Wnt/β-catenin signaling is to use specific inhibitors. Developing drugs that modulate Wnt/β-catenin signaling has been a focus for decades, but to date has not been clinically successful [38]. In syngeneic mouse-tumor-models, β-catenin inhibition with CTNNB1 Dicer siRNA (DCR-BCAT) significantly increased T-cell infiltration, and potentiated the sensitivity to immune checkpoint inhibitors [39]. DCR-BCAT is an intravenously delivered lipid-nanoparticle containing oligonucleotide, which selectively silences CTNNB1 [40]. A number of non-coding RNAs (ncRNAs) can reportedly affect β-catenin levels in hepatocellular carcinoma, but have not reached clinical application [41]. In ongoing clinical trials, several Wnt/β-catenin inhibitors are also being investigated, in combination with immune checkpoint inhibitors (Table 1). One of the most promising Wnt/β-catenin signaling inhibitors is the porcupine (PORCN) inhibitor [42]. PORCN is indispensable for Wnt binding to its receptor Frizzled, which triggers Wnt/β-catenin signaling. In a phase-1 study in solid tumors combining WNT974, a PORCN inhibitor, and spartalizumab, an anti-PD-1 antibody, stable disease was reported in 53% of patients who were primary refractory to prior anti-PD-1 antibody treatment [43]. Another candidate drug is DKN-01, which is a humanized IgG4 monoclonal antibody that binds and neutralizes circulating Dickkopf-1 (DKK1). Secreted DKK1 is characterized as an inhibitor of the Wnt/β-catenin-dependent (canonical) pathway, but an activator of Wnt/β-catenin-independent (non-canonical) pathway signaling [44]. Because DKN-01 does not directly inhibit the Wnt/β-catenin pathway, it can reportedly enhance innate immunity rather than alter the T-cell-excluded tumor microenvironment to become an inflamed state [45]. The efficacy of DKN-01 was enhanced in combination with an anti-PD-1 antibody in a murine model of melanoma and metastatic breast cancer [45]. A phase-1b study of DKN-01 in combination with pembrolizumab in advanced esophagogastric cancer showed objective response rates of 50% in DKK1-high and 0% in DKK1-low patients [46]. These trials are being conducted on a variety of cancers.
Table 1. Current clinical trials combining a Wnt/β-catenin signaling inhibitor with an immune checkpoint inhibitor.
Drug Target ICI Agent Cancer Type Trial Phase Clinical Trial
LGK974 PORCN PDR001 Solid tumors I NCT01351103
ETC-1922159 PORCN Pembrolizumab Solid tumors I NCT02521844
CGX1321 PORCN Pembrolizumab Solid/GI tumors I NCT02675946
RXC004 PORCN Nivolumab Solid tumors I NCT03447470
RXC004 PORCN Nivolumab Colorectal cancer II NCT04907539
DKN-01 DKK1 Pembrolizumab Esophagogastric cancer I NCT02013154
DKN-01 DKK1 Nivolumab Biliary tract cancer II NCT04057365
DKN-01 DKK1 Atezolizumab Esophagogastric cancer I/II NCT04166721
DKN-01 DKK1 Tiselizumab Esophagogastric cancer II NCT04363801
PORCN, Porcupine; DKK1, Dickkopf-1; GI, gastrointestinal.

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Satoshi Muto
,
Akio Enta
,
Yoshiyuki Maruya
,
Sho Inomata
,
Hikaru Yamaguchi
,
Hayato Mine
,
Hironori Takagi
,
Yuki Ozaki
,
Masayuki Watanabe
,
Takuya Inoue
,
Takumi Yamaura
,
Mitsuro Fukuhara
,
Naoyuki Okabe
,
Yuki Matsumura
,
Takeo Hasegawa
,
Jun Osugi
,
Mika Hoshino
,
Mitsunori Higuchi
,
Yutaka Shio
,
Kazuyuki Hamada
,
Hiroyuki Suzuki
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Update Date: 31 Jan 2023
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