J Exp Clin Canc Res: A new breakthrough in cancer immunotherapy-CD112R/CD112 axis

，(ICIs)，
。FDAIpilimumab，T-4 (CTLA-4)，
。PD-1，
。

Recently, the potential of immune checkpoint inhibitors (ICIs) to treat certain types of cancer has been confirmed, and encouraging results have been achieved
.

Ipilimumab, an antibody against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), approved for use by the FDA , is considered a milestone in cancer treatment

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However, a large number of cancer patients either failed to respond to these single immune checkpoint suppression therapies, or developed drug resistance after the initial response
.

Other new therapies that co-inhibit receptor pathways targeting nectin and its related families (such as CD96, T cell immunoglobulin and ITIM domain (TIGIT) and CD112R) have been validated in cancer immunotherapy

However, a large number of cancer patients either failed to respond to these single immune checkpoint suppression therapies, or developed drug resistance after the initial response

In a subset of normal human peripheral blood cells, the CD112R gene is expressed in NK cells and T lymphocytes, but in monocyte-derived dendritic cells (DCs), neutrophils (CD66b+), and monocytes (CD14+) It is not expressed in B cells (CD19+)
.

Most T cells expressing CD112R are CD8+ T cells, mainly effector/memory cells

In a subset of normal human peripheral blood cells, the CD112R gene is expressed in NK cells and T lymphocytes, but in monocyte-derived dendritic cells (DCs), neutrophils (CD66b+), and monocytes (CD14+) It is not expressed in B cells (CD19+)

In various solid tumors, NK cells, CD8+ T cells, and CD4+ T cells all have CD112R expression, with the highest expression levels
in the kidney, ovary, lung, prostate and endometrium .

In addition, it is expressed in T cells and NK cells of acute myeloid leukemia

In various solid tumors, NK cells, CD8+ T cells, and CD4+ T cells all have CD112R expression, with the highest expression levels

CD112, also known as nectin-2 or pvr2-related protein 2 (PVRL2), is a member of the nectin family and has been reported to be associated with tumor angiogenesis , growth and metastasis

In humans, CD112R is expressed on T cells and NK cells in many types of tumors, and the CD112R/CD112 axis is known to hinder the immune function of T cells

The CD112R-CD112 pathway plays an important role in regulating the killing of tumor cells by T cells
.

In cd112r-deficient melanoma and colon cancer mouse models, tumor growth stopped

The CD112R-CD112 pathway plays an important role in regulating the killing of tumor cells by T cells

Blocking human CD112R helps the anti-tumor effect of NK cells and inhibits tumor growth
.
Early or late CD112R blockade can effectively inhibit tumor growth and prolong the survival time of tumor-bearing mice.
This is related to the frequency of NK cells infiltrating tumors and the enhanced cytotoxic potential
.
Both NK cells and CD8+ T cells play an important role in the anti-tumor effect of CD112R blockade.
Even in the case of adaptive immunodeficiency, the anti-tumor effect still exists
.

CD112 is especially highly expressed in lung cancer, breast cancer and ovarian cancer
.
CD112 is expressed in PD-L1(−) and PD-L1(+) tumors in breast, ovary and lung tissues; therefore, the CD112R-CD112 axis can inhibit T cell function in PD-L1− tumors
.
These findings indicate that it is necessary to develop a new treatment strategy to treat PD-L1(-) tumors or cancer patients who are resistant to other immune checkpoint inhibitors by targeting CD112/CD112R
.

CD112 is especially highly expressed in lung cancer, breast cancer and ovarian cancer
.
CD112 is expressed in PD-L1(−) and PD-L1(+) tumors in breast, ovary and lung tissues; therefore, the CD112R-CD112 axis can inhibit T cell function in PD-L1− tumors
.
These findings indicate that it is necessary to develop a new treatment strategy to treat PD-L1(-) tumors or cancer patients who are resistant to other immune checkpoint inhibitors by targeting CD112/CD112R
.
It is necessary to develop a new treatment strategy to treat PD-L1(-) tumors or cancer patients who are resistant to other immune checkpoint inhibitors by targeting CD112/CD112R
.

The relationship between CD112R expression and cancer prognosis

In many types of tumors, CD112R is expressed in NK cells and T cells
.
Nevertheless, only a few studies have focused on the impact of CD112R on the prognosis of cancer
.
Qiao et al.
studied the expression profile characteristics of 553 HCC patients from the TCGA and GEO databases, including 8 genes (DCAF13, FAM163A, GPR18, LRP10, CD112R, S100A9, SGCB and TNNI3K), which can predict the survival of patients
.
According to this genetic map, liver cancer patients can be divided into high-risk groups and low-risk groups
.
The expressions of GPR18, CD112R, and TNNI3K were up-regulated in patients with low-risk scores, while the expressions of DCAF13, FAM163A, LRP10, SGCB, and S100A9 were down-regulated
.
The prognosis of patients with low risk score was significantly better than that of patients with high risk score (2.
20 years vs.
8.
93 years)
.

Qiao et al.
studied the expression profile characteristics of 553 HCC patients from the TCGA and GEO databases, including 8 genes (DCAF13, FAM163A, GPR18, LRP10, CD112R, S100A9, SGCB and TNNI3K), which can predict the survival of patients
.
According to this genetic map, patients with liver cancer can be divided into high-risk groups and low-risk groups
.
The expressions of GPR18, CD112R, and TNNI3K were up-regulated in patients with low-risk scores, while the expressions of DCAF13, FAM163A, LRP10, SGCB, and S100A9 were down-regulated
.
The prognosis of patients with low risk score was significantly better than that of patients with high risk score (2.
20 years vs.
8.
93 years)
.

CD112 expression as a diagnostic and prognostic biomarker

diagnosis

More and more preclinical and clinical studies have emphasized the role of CD112 in tumor progression and highlighted its impact on tumor prognosis
.
CD112 expression has been enhanced in several cancer types, and its overexpression is correlated with different tumor outcomes of different types of tumors (Table 3), and it has a strong prognostic effect on the operating system and progression-free survival (PFS) of certain cancers
.

(1) Gallbladder cancer

(1) Gallbladder cancer

Kaplan-Meier survival analysis of patients with SC/ASC ( squamous cell/adenosquamous carcinoma) and AC ( adenocarcinoma) showed that high CD112 expression levels are a strong and independent predictor of shorter survival time
.
Therefore, in AC and SC/ASC patients, CD112 expression is associated with aggressiveness and poor prognosis
.

Kaplan-Meier survival analysis of SC/ASC ( squamous cell/adenosquamous carcinoma) and AC ( adenocarcinoma) patients showed that high CD112 expression levels are a strong and independent predictor of shorter survival time
.
Squamous cell/adenosquamous carcinoma) adenocarcinoma) Therefore, in patients with AC and SC/ASC, CD112 expression is associated with aggressiveness and poor prognosis
.

(2) Liver cancer

(2) Liver cancer

A recent study showed that CD112 is significantly higher in hepatocellular carcinoma tissues than in neighboring tissues
.
In the Nectin-2 (CD112) KO mouse liver cancer model, by restoring T cell infiltration and slowing down T cell depletion, liver cancer tumors are significantly smaller
.
In addition, high expression of CD112 was also observed in liver metastases of colorectal cancer
.

A recent study showed that CD112 is significantly higher in hepatocellular carcinoma tissues than in neighboring tissues
.
In the Nectin-2 (CD112) KO mouse liver cancer model, by restoring T cell infiltration and slowing down T cell depletion, liver cancer tumors are significantly smaller
.
In addition, high expression of CD112 was also observed in liver metastases of colorectal cancer
.
By restoring T cell infiltration and slowing down T cell exhaustion, liver cancer tumors become significantly smaller
.
In addition, high expression of CD112 was also observed in liver metastases of colorectal cancer
.

(3) Lung cancer

(3) Lung cancer

CD112 and nectin-4 can be used to diagnose lung cancer
.
According to reports, CD112 is a stronger diagnostic indicator, but it cannot be used as a prognostic or predictive indicator
.
The researchers also found that compared with the control group, the serum CD112 concentration of cancer patients was significantly up-regulated, and the sensitivity (91.
9%) and specificity (92.
5%) of serum CD112 were higher than that of serum nectin-4 (sensitivity 70%; specificity 85 %), or combined use of serum CD112 and nectin-4 (sensitivity 80%; specificity, 87%)
.
Therefore, the serum CD112 concentration is more effective in identifying whether an individual has lung cancer
.
However, serum CD112 and nectin-4 levels have nothing to do with clinicopathological parameters, OS or PFS
.

CD112 and nectin-4 can be used to diagnose lung cancer
.
According to reports, CD112 is a stronger diagnostic indicator, but it cannot be used as a prognostic or predictive indicator
.
The researchers also found that compared with the control group, the serum CD112 concentration of cancer patients was significantly up-regulated, and the sensitivity (91.
9%) and specificity (92.
5%) of serum CD112 were higher than that of serum nectin-4 (sensitivity 70%; specificity 85 %), or combined use of serum CD112 and nectin-4 (sensitivity 80%; specificity, 87%)
.
Therefore, the serum CD112 concentration is more effective in identifying whether an individual has lung cancer
.
However, serum CD112 and nectin-4 levels have nothing to do with clinicopathological parameters, OS or PFS
.
CD112 and nectin-4 can be used to diagnose lung cancer
.
According to reports, CD112 is a stronger diagnostic indicator, but it cannot be used as a prognostic or predictive indicator
.
The researchers also found that compared with the control group, the serum CD112 concentration of cancer patients was significantly up-regulated, and the sensitivity (91.
9%) and specificity (92.
5%) of serum CD112 were higher than that of serum nectin-4 (sensitivity 70%; specificity 85 %), or combined use of serum CD112 and nectin-4 (sensitivity 80%; specificity, 87%)
.
Therefore, the serum CD112 concentration is more effective in identifying whether an individual has lung cancer
.
However, serum CD112 and nectin-4 levels have nothing to do with clinicopathological parameters, OS or PFS
.
However, serum CD112 and nectin-4 levels have nothing to do with clinicopathological parameters, OS or PFS
.

(4) Acute myeloid leukemia

(4) Acute myeloid leukemia

One study reported that CD155 and CD112 may be negative prognostic markers for acute myeloid leukemia (AML)
.
High CD112 expression levels are associated with lower RFS (p = 0.
017)
.
The OS of patients with high expression levels of CD155 and CD112 seems to be significantly lower than that of the low expression group
.

(P

(5) Colorectal cancer

(5) Colorectal cancer

In one study, CD112 expression in serum has diagnostic value for patients with colorectal cancer (CRC); it may have poor prognostic value in non-metastatic patients
.
The serum expression level of CD112 in CRC patients was significantly higher than that in healthy controls
.
Compared with lower levels, elevated CD112 concentrations had a significant adverse effect on PFS (median 5.
8 and 9.
1 months, respectively: p  = 0.
04)
.
Although elevated serum levels of CD112 had a significant adverse effect on the PFS of non-metastatic patients (median 6.
0 and 14.
0 months, respectively: p = 0.
05), there was no such effect on patients with metastases
.
The CD112 serum level had no significant adverse effect on the OS of all patients (p = 0.
14)
.
In addition, the serum level of CD112 does not seem to have any significant effect on OS in non-metastatic and metastatic patient populations ( p  = 0.
32 and p  = 0.
07, respectively)
.

p p (p are respectively p p

(6) Ovarian cancer

(6) Ovarian cancer

The results showed that in 60 ovarian cancer patients, the high expression of CD112 was related to lymph node metastasis and residual tumors after surgery
.
Although there are no significant differences between tumor grade, receptor status, or metastasis, CD112 is overexpressed in ovarian cancer tissues and various human ovarian cancer cell lines
.
In addition, patients with postoperative lymph node metastasis or residual tumors have higher CD112 gene expression levels than patients with complete tumor resection
.
Therefore, CD112 in ovarian cancer expresses or supports tumor cell adhesion, promotes tumor growth and lymph node metastasis
.

(7) Pancreatic ductal adenocarcinoma

(7) Pancreatic ductal adenocarcinoma

Among 106 pancreatic ductal adenocarcinomas (PDAC), high CD112 andThe expression level of DDX3 is related to poor prognosis and progression
.
The expression rate of CD112 and DDX3 in PDAC tumor tissues was significantly higher than that of proximal membranous tissues, benign lesions and healthy pancreatic tissues
.
Patients with poor differentiation, invasion of surrounding tissues and organs, lymph node metastasis, and TNM stage III and IV disease have higher levels of CD112 and DDX3 than well-differentiated tumors, no invasion, no lymph node metastasis, and TNM first and second stages Disease patients
.
Compared with patients with negative expression of CD112 and DDX3, patients with positive expression of CD112 and DDX3 have a shorter survival time, and both CD112 and DDX3 are independent prognostic factors
.
However, in another study on the prognosis of PDAC, a different conclusion emerged: CD112 expression has nothing to do with OS
.

CD112 expression has nothing to do with OS
.

In general, high CD112 expression is related to the aggressiveness and poor prognosis of gallbladder cancer, AML, and ovarian cancer
.
Serum CD112 levels have diagnostic value in lung cancer and CRC, and high levels are associated with poor prognosis of CRC
.
However, its influence on the prognosis of PDAC and HCC needs to be further explored
.

High CD112 expression is related to the aggressiveness and poor prognosis of gallbladder cancer, AML and ovarian cancer
.
Serum CD112 levels have diagnostic value in lung cancer and CRC, and high levels are associated with poor prognosis of CRC
.
However, its influence on the prognosis of PDAC and HCC needs to be further explored
.

 

In summary, with the discovery of ICIs, cancer immunotherapy research has reached an important milestone
.
However, due to potential primary and secondary drug resistance, a considerable number of cancer patients have not benefited from these new immune checkpoint inhibitor approaches
.
Different ICIs and their pathways may exhibit different functions in different tumor microenvironments
.
Therefore, it is very important to accurately map the expression profile of each pathway in different types of tumors to determine the most appropriate treatment method to ensure the best results
.

In summary, with the discovery of ICIs, cancer immunotherapy research has reached an important milestone
.
However, due to potential primary and secondary drug resistance, a considerable number of cancer patients have not benefited from these new immune checkpoint inhibitor approaches
.
Different ICIs and their pathways may exhibit different functions in different tumor microenvironments
.
Therefore, it is very important to accurately map the expression profile of each pathway in different types of tumors to determine the most appropriate treatment method to ensure the best results
.
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