Serum autoantibody-based biomarkers for prognosis in early-stage lung cancer patients with surgical resection

doi:10.21203/rs.3.rs-4851079/v1

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Serum autoantibody-based biomarkers for prognosis in early-stage lung cancer patients with surgical resection

https://doi.org/10.21203/rs.3.rs-4851079/v1

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Background

Lung cancer is the cancer with the highest morbidity and mortality in the world. Autoantibodies have been widely used as biomarkers for detection of lung cancer. With the increasing diagnosis rate of patients with early-stage lung cancer, surgery has become the first-line treatment for more patients. However, there is a lack of effective indicators to assess the risk of recurrence after lung cancer surgery.

Methods

We collected levels of serum autoantibodies (MAGEA1, GAGE7, GBU4-5, CAGE, SOX2, P53 and PGP9.5) and evaluated their roles as biomarkers especially for postoperative recurrence of lung cancer. In vitro experiments including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) were performed to explore the functions of serum autoantibodies.

Results

Our study demonstrated that serum autoantibody-positive patients with early-stage lung cancer had a longer postoperative progression period. The levels of serum autoantibodies in patients with lung cancer were higher than that in patients with benign lung diseases. Additionally, MAGEA1 exhibited higher levels in lung squamous cell carcinoma (LUSC) than that in lung adenocarcinoma (LUAD) but all the serum autoantibodies had no difference between patients with stage I and II. In addition, the results of in vitro experiments indicated that serum autoantibodies can mediate immune responses and enhance anti-tumor effects.

Conclusion

This study proposed effective biomarkers for prognosis in lung cancer patients after surgery which is critical to reduce the recurrence. Besides, the anti-tumor effect of serum autoantibodies may provide a new strategy for the treatment of lung cancer.

autoantibody

lung cancer

biomarker

surgery

prognosis

This study revealed that the autoantibodies overexpressed in early-stage lung cancer patients have a significantly better prognosis after surgery which can be promising prognostic markers. Besides, we illustrated the anti-tumor properties of the serum autoantibodies which may enhance the anti-cancer immunity of the early-stage lung cancer patients.

Lung cancer is currently the most common and fatal cancer in the world [1]. According to pathological classification, it can be divided into two types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), of which non-small cell lung cancer accounts for about 85% [2, 3]. At present, the proportion of stage I and stage II lung cancer patients is 17.3% and 15.2%, respectively, and this proportion is gradually increasing with the development of early screening technology for lung cancer[4]. Surgery is the first-line treatment for early-stage lung cancer, but the prognosis for surgery varies from person to person [5, 6]. If there is a marker that can predict the probability of recurrence, we can make pre-operative and post-operative planning to more effectively reduce the recurrence rate. Therefore, it is urgent to explore an effective marker to evaluate the surgical prognosis of early-stage lung cancer patients.

The sensitivity of traditional markers as early diagnosis of lung cancer is not high [7]. As a result, it is even more difficult to develop them as an indicator of surgical prognosis in patients with early-stage lung cancer. Compared with traditional tumor markers, tumor-related autoantibodies have higher sensitivity and specificity and are more suitable for the diagnosis early-stage lung cancer [8, 9]. The autoantibodies were reported to be detectable even before the appearance of disease symptoms. For instance, high expression of the tumor-associated autoantibody p53 can be detected in patients with lung cancer before clinical manifestations appear [10, 11]. There are many different panels of autoantibodies for early diagnosis of lung cancer and the panel consisting of MAGEA1, GAGE7, GBU4-5, CAGE, SOX2, P53 and PGP9.5 has been used in clinical lung cancer screening [12]. Recently, there are studies revealed the relationship between the level of serum autoantibodies and prognosis. For example, breast cancer patients and lung cancer patients with autoantibodies had longer progression-free survival time and overall survival time than those without autoantibodies [13, 14]. However, there are few studies to evaluate the autoantibodies as prognostic biomarkers for patients with surgical treatment.

Autoantibodies not only serve as biomarkers of cancers, but may have specific functions during the progression of cancers [15, 16]. Antibodies are well-known for their roles in mediating immune reactions, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). As a result, serum cancer related autoantibodies may be protective for patients and may exhibit antitumor effect [17]. There are many articles revealed the values of autoantibodies for the diagnosis of cancers, but few studies explored their antitumor functions. Here, we preliminarily investigated the anti-tumor effects of serum autoantibodies through in vitro experiments.

This study aims to explore the feasibility of autoantibodies as markers for surgical prognosis in patients with early-stage lung cancer. Furthermore, we illustrated the antitumor function of serum autoantibodies with in vitro experiments.

2.1 Patients

This study was a single-center retrospective study conducted in the First Affiliated Hospital of University of Science and Technology of China. Patients treated with thoracic surgery and diagnosed with primary lung cancer between September 2019 and December 2023 were enrolled in the study. A total of 412 patients with benign lung diseases and 1336 patients with lung cancer were enrolled. The stage was classified according to the eighth edition of lung cancer staging classification statistics [18]. Inclusion criteria were the following: (1) patients with benign lung disease or lung cancer and diagnosed by pathology or needle biopsy, (2) patients with TNM classification of stage I-II, (3) patients ages are more than 15 years, (4) patients are treated with thoracic surgery. Exclusion criteria were the following: (1) patients are not primary lung cancer (n = 4), (2) patients have no clear lung pathological diagnosis (n = 9), (3) patients with TNM classification of stage Ⅲ-Ⅳ (n = 139), (4) patients have an autoimmune disease (n = 5). This study was approved by the Ethics Committee of the Western District of the First Affiliated Hospital of the University of Science and Technology of China (2024054).

2.2 Sample collection

Blood samples were collected from enrolled patients. Serum was isolated and stored at -80°C for subsequent experiments. Autoantibody concentrations were quantified with autoantibody (MAGEA1, GAGE7, GBU4-5, CAGE, SOX2, P53 and PGP9.5) detection kits (Cancer Probes, China). The normal reference ranges of autoantibodies were as follows: MAGEA1: 0ཞ11.9 U/ml, GAGE7: 0ཞ14.4 U/ml, CAGE: 0ཞ7.2 U/ml, GBU4-5: 0ཞ7.0 U/ml, SOX2: 0ཞ10.3 U/ml, P53: 0ཞ13.1 U/ml, PGP9.5: 0ཞ11.1 U/ml. The patients are considered antibody negative unless the level of any one of the antibodies exceeds the threshold.

2.3 Cell culture

Human lung cancer cell lines H82 (#HTB-175™) and H1299 (#CRL-5803) were purchased from ATCC and identified by STR. THP-1 and NK-92 were supplied by Wei Hai Ming professor. H82 and H1299 were cultured in RPMI-1640 (BioChannel Biological Technology Co., Ltd., BC-M-017, Nanjing, China) medium containing 10% Fetal Bovine Serum (FBS) (BioChannel Biological Technology Co., Ltd., BC-SE-FBS07, Nanjing, China), 1% penicillin-streptomycin solution (BioChannel Biological Technology Co., Ltd., BC-ce-007, Nanjing, China). THP-1 cells were cultured in macrophage cell medium (Pricella, CM-0233, Wuhan, China), containing 10% FBS (164210-50), 0.05 mM β-mercaptoethanol and 1% penicillin-streptomycin solution (PB180120). NK-92 cells were cultured in natural killer cell medium (EK-Bioscience, CC-Y1400M), containing MEM-α, 0.2 mM myonositol, 0.1 mM β-mercaptoethanol, 0.02 mM folic acid, 100 U/mL recombinant IL-2, 12.5% Horse serum, 12.5% FBS and 1% penicillin-streptomycin solution. All cell lines were not contaminated with mycoplasma and cultured in a 37°C incubator containing 5% CO2.

2.4 Immunohistochemical staining

Formalin-fixed lung tissue sections are re-hydrated using a graded ethanol solution. Extract in 10 mm citric acid buffer at 98–100°C for 30 min. Non-specific binding was blocked by 10% normal goat serum for 30 min. The primary antibody of MAGEA1 (NOVUS, NBP3-22211, Colorado, USA) (1:200) were added on the section overnight at 4°C, followed by incubation with HRP-conjµgated goat anti-mouse secondary antibody (Immunoway, RS0011, California, USA) for 30 min at room temperature. Photographs were taken using a fluorescence microscope (Olympus IX73, Tokyo, Japan) and analyzed with Image J software.

2.5 Antibody-dependent cellular cytotoxicity (ADCC)

5×10⁶ H82 cells were mixed with Calcein-AM (MCE, HY-D0041, Shanghai, China) for 25 min at 37°C. After washed with PBS, 3×10⁵ cells/ml of H82 cells were prepared and used as the target cells. 6×10⁶ cells/ml of NK-92 cells were used as effector cells. Equal volumes of target and effector cells were mixed (concentration ratio equivalent to 1:20) and transferred to 96-well plates. Serum containing anti-MAGEA1 autoantibody was used as the antibody for the in vitro test (ADCC, CDC and ADCP). Then, 20 µl of serum with different dilution gradients (Undiluted, 1:2, 1:5, 1:10) was added to the 96-well. In the control group, 20 µl of PBS was used instead of the serum. After incubated for 4 hours in 37°C, mixture (50 µl) of Propidium Iodide (PI) (MCE, HY-D0815, Shanghai, China) and Calcein-AM (MCE, HY-D0041, Shanghai, China) was added and incubated at 37°C for another 30 min. Photographs were taken using a fluorescence microscope (Olympus IX73, Tokyo, Japan) and analyzed with Image J software.

2.6 Antibody-dependent cellular phagocytosis (ADCP)

THP-1 cells were maintained in 6-well plates (1×10⁶ cells per well) and 100 ng/ml of phorbol myristate acetate (PMA) (MCE, HY-18739, Shanghai, China) was added and incubated in a 37°C incubator for 48 hours to generate macrophages (labeled as M0). M0 macrophages have the function of engulfing and removing cellular debris, and are the starting point of inflammatory response. M0 macrophage was then cultured in 24-well plates (1×10⁵ cells per well) and incubated in a 37°C incubator for 24 hours. Then, 100 ng/ml LPS (MCE, HY-D1056, Shanghai, China) and 20 ng/ml IFN-γ (MCE, HY-P7025, Shanghai, China) were added to drive the M0 macrophages polarization to the M1 phenotype and incubated in 37°C for 48 hours. M1 type macrophages produce a large number of inflammatory factors and have the effect of promoting inflammatory response. Then 20 µl serum which positive for anti-MAGEA1 autoantibodies was added in different dilution gradients (undiluted, 1:2, 1:5, 1:10). In the control group, 20 µl of PBS was used instead of the serum. After incubation at 37°C for 45 min, Calcein-AM (MCE, HY-D0041, Shanghai, China)-labeled H82 cells (3×10⁵ cells per well) were added and cultured for 6 hours. Photographs were taken using a fluorescence microscope (Olympus IX73, Tokyo, Japan) and analyzed with Image J software.

2.7 Complement-dependent cytotoxicity (CDC)

H1299 cells were plated in 96-well plates (1×10⁴ cells per well) in RPMI-1640 medium containing 1% FBS. After 24 hours, the supernatant was discarded and 25 µl serum which positive for anti-MAGEA1 autoantibodies with different concentration gradients (undiluted, 1:2, 1:5, 1:10) was add for 15 min. Then, 50 µl of fresh rabbit complement (Cedarlane, CL3051, Canadian) was added and incubated at 37°C for 2 hours. All medium were then discarded and replaced with medium (100 µl per well) containing 10% CCK8 (Beyotime, C0038, Shanghai, China). After incubation at 37°C for 2 hours the absorbance was detected by the Multiskan FC Microplate reader (Thermo, Massachusetts, USA).

2.8 Statistical analysis

Statistical analyses were performed using GraphPad Prism 7 software and ImageJ. Group differences in the concentrations of autoantibodies were analyzed with the log-rank (Mantel-Cox) test and t-tests with or without Welch’s correction. P < 0.05 was considered statistically significant.

3.1 Patient Information

As show in Fig. S1, a total of 1748 patients including 412 patients with benign lung diseases and 1336 patients with early-stages lung cancer were included in this study. Comprehensive clinical information for the enrolled participants, including age, gender, tumor type, and tumor stage were summarized in Table 1. The median age of benign lung diseases patients and lung cancer patients were 55 and 57, respectively. A total of 1228 patients with LUAD were included in this study, accounting for 89.89%, 95 patients with LUSC accounted for 6.95%, and 13 patients with SCLC accounted for 0.95%. In addition, the patients with early-stage lung cancer were reclassified into stage I (92.9%) and stage II (4.83%) according to the eighth edition of the TNM classification for lung cancer [18].

Table 1

Basic information of patients
Patient characteristics
Number	1336	412
Gender (%)
Male	582 (42.60%)	236 (57.28%)
Female	754 (55.19%)	176 (42.71%)
Age, years
Median, range	57(17–92)	55(15–95)
Patient type (%)
LUAD	1228 (89.89%)
LUSC	95 (6.95%)
SCLC	13 (0.95%)
Stage (%)
Ⅰ	1270 (92.97%)
Ⅱ	66 (4.83%)

3.2 Different levels of autoantibodies in patients with benign lung diseases and lung cancer

The levels of the seven serum autoantibodies were analyzed in 412 patients with benign lung diseases and 1366 patients with early-stage lung cancer. Compared with patients with benign lung diseases, the serum autoantibodies levels of MAGEA1, GAGE7, GBU4-5 and CAGE were higher in patients with lung cancers (P < 0.0001, P = 0.0020, P = 0.0108, P = 0.0368) (Fig. 1).

3.3 The expression of autoantibodies in patients with different types of lung cancers

To observe whether the levels of serum autoantibody in patients correlated with the histological type of the patients, we compared the levels of autoantibodies in patients with LUAD, LUSC and SCLC. MAGEA1, SOX2 and PGP9.5 have significant differences between LUAD and LUSC (P = 0.0004, P = 0.0057, P = 0.0402) (Fig. 2). In addition, the expression levels of GAGE7 were higher in LUAD than SCLC (P = 0.0003) (Fig. 2). However, the proportion of patients with SCLC is too small (0.95%) and may not reflect the actually tendency of autoantibodies in patients with SCLC. Clinically, it is more desirable to distinguish the pathological type of lung cancer through the expression of positive antibodies. However, the proportion of patients with elevated autoantibodies is not very high. As a result, we focused on patients with LUAD and LUSC with positive autoantibody levels. We compared the serum autoantibody levels in LUSC and LUAC patients with positive serum autoantibody expression and found that only the expression of MAGEA1 autoantibody in LUSC was higher than that in LUAD (P = 0.0064) (Fig. S2).

3.4 The expression of autoantibodies in different stages of lung cancer

To further understand the effect of autoantibodies on disease progression, we compared seven autoantibodies’ levels (MAGEA1, GAGE7, GBU4-5, CAGE, SOX2, P53 and PGP9.5) between lung cancer patients with stage I and stage II. The results showed that there was no difference in autoantibody expression between the two groups (P = 0.875, P = 0.0728, P = 0.8033, P = 0.4289, P = 0.1166, P = 0.6714, P = 0.2086) (Fig. 3).

3.5 Autoantibody-based biomarker for prognosis prediction in lung cancer patients with surgical resection

In order to further explore the relationship between autoantibodies and the prognosis of patients with early-stage lung cancer after surgery, we conducted the progression-free survival (PFS) analysis of patients. As many enrolled patients above were not treated in this hospital and could not provide enough information for PFS analysis, only 154 patients with positive-autoantibodies were picked out here. Then, we randomly selected comparable number of autoantibody-negative patients for the PFS analysis. The progression period for patients with positive-autoantibodies ranges from 3 to 54 months (median, 16 months), while that for patients with negative-autoantibodies ranges from 1 to 51 months (median, 12 months) (P < 0.0001, Fig. 4A). Besides, we further compared these patients’ progression within one or three years (Fig. 4B-C). The results showed that 24% of patients (n = 13) with positive-autoantibody expression progressed in one year, while 41% of patients (n = 33) with negative-autoantibody expression progressed in one year (Fig. 4B). Within three years, there are 22% of patients (n = 28) with positive-autoantibody expression progressed, while 48% of patients (n = 66) with negative-autoantibody expression progressed (Fig. 4C). This result showed that longer PFS was observed in autoantibodies-positive patients which exhibited great potential as a prognostic maker for lung cancer surgery.

3.6 The anti-tumor effects of autoantibodies

Since the antibody need to enter the tumor tissue to function, we further explored whether IgG was expressed in the tumor tissues from serum autoantibody-positive patients. We chose three lung cancer patients who were serum autoantibody-positive and their information are provided in Table S1. Immunohistochemistry was used to detected IgG protein expression in lung cancer tissues specimens. The results indicated that patients with positive serum autoantibody expression were also positive for IgG in the pathological tissues (Fig. 4D). Generally, antibodies could bind to corresponding antigens and exert immune effects through ADCC, ADCP and CDC [19, 20]. As anti-MAGEA1 autoantibodies showed more significant difference between lung cancer and benign lung diseases, we choose the anti-MAGEA1 autoantibodies to explore the serum autoantibody function. Here, certain cells (H1299 and H82 which have higher MAGEA1 expression) were used to evaluate the anti-tumor effects of serum autoantibodies of MAGEA1 from patients [21]. Besides, H1299 is a kind of adherent cells and suitable for ADCC and CDC experiments, while H82 is a kind of suspension cell which more suitable for ADCP experiment. In the test of CDC, we counted the cells by fluorescence and found that the higher the serum autoantibody concentration, the more apoptotic cells (red cells) there were (Fig. 5A-B). Besides, through the CCK8 experiment, it was found that the lower the concentration of antibodies, the higher the cell viability. The results of the two experiments were consistent which illustrated the serum autoantibodies could mediate the CDC effect toward tumor cells. (Fig. 5C). In the test of ADCP, with the concentration of serum autoantibody increased, the number of phagocytosed H82 cells also increased (Fig. 5D-E). Similarly, in the ADCC experiments, we also found that ratio of the apoptosis cells (red fluorescence) in total cells (red and green fluorescence) was higher as the concentration of the serum autoantibody increased (Fig. 5F-G). In general, these tests all validated the anti-tumor effects of serum autoantibodies from patients.

Lung cancer is the most common cancer in our country and the leading cause of cancer death [22]. With the development of early screening for lung cancer, approximately 30% of patients are diagnosed at early stage [4]. The primary therapeutic approach for individuals diagnosed with early-stage lung cancer is surgical intervention although postoperative recurrence is common [23–25]. However, there is a lack of reliable prognostic indicators for early-stage lung cancer after surgery which is one of the reasons for the high recurrence after surgery.

In the study, we first compared the levels of serum autoantibodies between patients with lung cancer and benign lung diseases. The results showed that the levels of most autoantibodies were higher in the lung cancer patients which were consistent with previous studies and validated the feasibility of our method for detecting antiantibodies [26]. Our primary objective is to determine the biomarkers of surgical prognosis for lung cancer patients which most in early-stage. As a result, patients diagnosed with stage I and stage II lung cancer were enrolled in this study. It was found that while the levels of certain autoantibodies varied between different types of cancer, there was no variance for all of the autoantibodies between stage I and stage II. The results revealed differences in the expressions of MAGEA1, SOX2, and PGP9.5 in LUAD and LUSC, as well as variances in GAGE7 expression between LUAD and SCLC. These results suggest that certain autoantibodies may be used to assist in distinguishing lung cancer types. However, some other studies have shown that serum autoantibodies expression is not associated with the type of lung cancer patients [13, 27]. These differences might be partly explained by the different selection criteria that we focused on patients diagnosed with early-stage lung cancer. Besides, the SCLC patients included are too small and may result in a sight bias in the results. Analysis of the progression free time of patients with negative and positive serum autoantibodies expression found that the patients with positive serum autoantibodies expression had a long progression period. This result indicated that the levels of serum autoantibodies may be developed as a promising biomarker for predicting postoperative outcomes for early-stage lung cancer patients. Similar associations have been observed in other cancers. For example, anti-Ro52 antibodies are common among ovarian cancer patients and their presence has been linked to a good prognosis [28]. Plasmacytoid ovarian cancer patients with higher serum p53 autoantibody expression before surgery had a higher overall survival rate than those with low P53 expression [29]. Serum NY-ESO-1 antibody is a good predictive biomarker for the assessment of recurrence after surgery in patients with gastric cancer [30]. Due to the lack of survival information in these patients, an analysis on the relationship between patient survival and serum autoantibody expression was not conducted in this study. Future follow-up studies will continue to monitor patient survival outcomes and explore this relationship further. Besides, a relative multi-center study would be conducted and additional validation cohort will be tested to further confirmed the results here.

The roles of autoantibodies are most studied in autoimmune diseases [31, 32]. However, few studies directly illustrated the function of tumor related autoantibodies. There are many clinical data suggested the presence of autoantibodies are benefit to cancer patients. For instance, the presence of autoantibodies has been associated with a good prognosis in patients with breast and ovarian cancer [28, 33]. In addition, the studies of tumor vaccine are aimed to stimulate the production of specific antibodies which could induce systemic tumor regression and prolong patient survival time [23, 34]. As we know, antibody can mediate immune responses including ADCC, ADCP and CDC to protect the body [35]. Therefore, we assumed that the autoantibodies may have direct antitumor effect in early-stage lung cancer which can contribute to the better prognosis after surgery. The IHC staining of tissue slices from autoantibody positive patients showed the presence of IgG in the lung cancer tissue. The results demonstrated that the autoantibodies infiltrated in the tumor microenvironment which laid the foundation for their antitumor effects. Next, in vitro experiments proved that serum autoantibodies of patients can mediate related immune responses and exert anti-tumor effects. However, in vitro studies do not adequately reflect the basic characteristics of tumor tissue and they lack the complex and dynamic cell-to-cell communication and cell-matrix interactions that occur during carcinogenesis [36]. In the future, we hope to further demonstrate the roles of tumor-associated autoantibodies in tumor progression through mouse models.

In conclusion, we demonstrated that the presence of autoantibodies indicating a better prognosis of early-stage lung cancer patients with treatment of surgery. The autoantibodies exhibited a robust potential as the biomarkers for the postoperative prognostic monitoring in early-stage lung cancer patients and may be further implemented in clinical practice. In addition, the results of in vitro experiments further elucidated the roles of autoantibodies in cancer progression which consistent with the clinical findings. The anti-tumor activity of these autoantibodies may allow them to be developed as drugs for use alone or in combination with other therapies.

Author contributions

Panpan Jiang: Conceptualization (equal); investigation(equal); writing – original draft (lead); writing review and editing (lead); in vitro experiment; Data curation. Kaili Wang: Data curation; in vitro experiment. Yaqin Wei: Immunohistochemistry experiment. Haonan Chen: Immunohistochemistry experiment. Xueqin Cai: Data curation. Yan Hua: Conceptualization (equal); investigation (equal); writing – review and editing (equal). Ming Li: Conceptualization (equal); writing – review and editing (equal).

Acknowledgement

The authors would like to thank the patients who participated in the trial, and the investigators and staff at all clinical study sites.

Funding information

This work was supported by Health Research Project of Anhui Province (No. AHWJ2023A10091), the Natural Science Foundation of Anhui Province (No. 2008085MH288), and the Major program of Education Department of Anhui Province (No. 2022AH040183).

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.

Data availability statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Human ethics approval declaration

This study was approved by the Ethics Committee of the Western District of the First Affiliated Hospital of the University of Science and Technology of China (2024054)

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Serum autoantibody-based biomarkers for prognosis in early-stage lung cancer patients with surgical resection

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Methods

Results

Conclusion

Figures

Summary at a glance

1. Introduction

2. Data and methods

2.1 Patients

2.2 Sample collection

2.3 Cell culture

2.4 Immunohistochemical staining

2.5 Antibody-dependent cellular cytotoxicity (ADCC)

2.6 Antibody-dependent cellular phagocytosis (ADCP)

2.7 Complement-dependent cytotoxicity (CDC)

2.8 Statistical analysis

3. Results

3.1 Patient Information

3.2 Different levels of autoantibodies in patients with benign lung diseases and lung cancer

3.3 The expression of autoantibodies in patients with different types of lung cancers

3.4 The expression of autoantibodies in different stages of lung cancer

3.5 Autoantibody-based biomarker for prognosis prediction in lung cancer patients with surgical resection

3.6 The anti-tumor effects of autoantibodies

4. Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1