Oncogenic cancer/testis antigens are a hallmarker of cancer and a sensible target for cancer immunotherapy

Abstract Introduction: Cancer/testis antigens (CTAs) are an attractive target for cancer immunotherapy because of a tumor-restricted expression and remarkable immunogenicity. Several CTAs have been used as a source of tumor antigen in dendritic cell therapy against multiple myeloma (MM), but there was no report the CTAs in Asian patients with MM. In this study, we evaluate the expression of 10 CTAs on malignant plasma cells of bone marrow in 18 Korean patients with relapsed or refractory MM. Materials and methods: Eighteen patients with relapsed or refractory MM were classified as four categories according to paraprotein subtypes: IgG (n=7), IgA (n=5), light chain-lambda (n=3), and light chain-kappa (n=3). The expression pattern of 10 CTAs, including NY-ESO-1, SSX2, SSX4, SSX5, MAGE-A3, MAGE-C1, MAGE-C2, BAGE2, CTAG2, and SPA7, was studied by real-time quantitative polymerase chain reaction in CD138+ cells of BM mononuclear cells (MNCs) obtained from MM patients. In addition, we compared it with expression pattern of CTAs in the MNCs from healthy normal donors and the CD138- cells of BM MNCs from MM patients as controls. Results: In CD138+ cells of BM MNCs from the patients, five CTAs, including SSX2, SSX4, MAGE-A3, MAGEC2, and CTAG2, showed high frequency and overall 5.4 to 63.9 fold increase expression in the quantitative mRNA survey compared to MNCs from healthy donors and CD138- cells of BM MNCs from patients. Expression pattern of 5 CTAs was slightly different by paraprotein subtypes: IgA subtype - SSX4 (17.1 fold increase), MAGE-A3 (11.0 fold increase), and CTAG2 (5.9 fold increase); IgG subtype - CTAG2 (63.9 fold increase), SSX4 (40.2 fold increase), and MAGE-A3 (39.9 fold increase); lambda light chain subtype - CTAG2 (42.4 fold increase), SSX4 (29.0 fold increase), and MAGE-A3 (24.4 fold increase); kappa light chain subtype - SSX2 (6.4 fold increase), MAGE-C2 (6.2 fold increase), MAGE-A3 (5.4 fold increase), and SSX4 (5.4 fold increase). Conclusion: This study suggests that three CTAs, such as SSX4, MAGE-A3, and CTAG2, highly expressed on malignant plasma cells are potentially promising targets for cancer immunotherapy in Korean patients with relapsed or refractory MM. Disclosures No relevant conflicts of interest to declare.

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Demethylation of Cancer/Testis Antigens and CpG ODN Stimulation Enhance Dendritic Cell and Cytotoxic T Lymphocyte Function in a Mouse Mammary Model

BioMed Research International ◽

10.1155/2013/196894 ◽

2013 ◽

Vol 2013 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Jun-Zhong Sun ◽

Lei Gao ◽

Li Gao ◽

Wei Wang ◽

Nan Du ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Target Cells ◽

Cytotoxic Lymphocytes ◽

Lymphocyte Function ◽

Cpg Odn ◽

Cancer Testis Antigens ◽

Cpg Oligodeoxynucleotide ◽

Immune Adjuvant ◽

Cancer Testis

Background. Cancer/testis antigens (CTAs) are ideal targets for cancer immunotherapy in virtue of their restricted expression profile in normal tissues. However, CTA-targeted immunotherapy has been rather disappointing clinical setting for CTAs are downregulated by cytosine-phosphate-guanosine (CpG) methylation in their promoter regions, so that tumor cells have low immunogenicity.Methods. We reinduced mouse CTA P1A through demethylation process and generated P1A-specific cytotoxic lymphocytes (CTLs) by immunizing BALB/c (H-2d) mice with dendritic cells pulsed with a P1A-specific peptide and CpG oligodeoxynucleotide (ODN) immune adjuvant.Results. We found that demethylation and CpG ODN immune adjuvant stimulation facilitated DC maturation and enhanced the allogenic capacity of P1A-specific CTLs against target cells bothin vitroandin vivo.Conclusions. Our results suggested that CTA induction and immune adjuvant stimulation is a feasible strategy in cancer immunotherapy.

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CANCER TESTIS ANTIGENS IN CANCER IMMUNOTHERAPY

Siberian Journal of Oncology ◽

10.21294/1814-4861-2017-16-2-71-81 ◽

2017 ◽

Vol 16 (2) ◽

pp. 71-81 ◽

Cited By ~ 2

Author(s):

D. I. Vodolazhsky ◽

O. I. Kit ◽

Kh. A. Mogushkova ◽

A. A. Pushkin ◽

N. N. Timoshkina

Keyword(s):

Cancer Immunotherapy ◽

Cancer Testis Antigens ◽

Cancer Testis

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Expression of Cancer-Testis Antigens in Stem Cells: Is it a Potential Drawback or an Advantage in Cancer Immunotherapy

Asian Pacific Journal of Cancer Prevention ◽

10.7314/apjcp.2015.16.7.3079 ◽

2015 ◽

Vol 16 (7) ◽

pp. 3079-3081 ◽

Cited By ~ 6

Author(s):

Soudeh Ghafouri-Fard

Keyword(s):

Stem Cells ◽

Cancer Immunotherapy ◽

Cancer Testis Antigens ◽

Cancer Testis

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Cancer-testis antigens: An update on their roles in cancer immunotherapy

Human Antibodies ◽

10.3233/hab-190366 ◽

2019 ◽

Vol 27 (3) ◽

pp. 171-183 ◽

Cited By ~ 1

Author(s):

Zahra Taherian-Esfahani ◽

Sepideh Dashti

Keyword(s):

Cancer Immunotherapy ◽

Cancer Testis Antigens ◽

Cancer Testis

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Expression of Cancer Testis Antigens in Tumor-Adjacent Normal Liver Is Associated with Post-Resection Recurrence of Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13102499 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2499

Author(s):

Lisanne Noordam ◽

Zhouhong Ge ◽

Hadiye Özturk ◽

Michail Doukas ◽

Shanta Mancham ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Normal Liver ◽

Occult Metastasis ◽

Recurrence Rates ◽

Curative Intent ◽

Cancer Testis Antigens ◽

Negative Prognostic Factor ◽

Increased Risk ◽

Hcc Recurrence ◽

Cancer Testis

High recurrence rates after resection of hepatocellular carcinoma (HCC) with curative intent impair clinical outcomes of HCC. Cancer/testis antigens (CTAs) are suitable targets for cancer immunotherapy if selectively expressed in tumor cells. The aims were to identify CTAs that are frequently and selectively expressed in HCC-tumors, and to investigate whether CTAs could serve as biomarkers for occult metastasis. Tumor and paired tumor-free liver (TFL) tissues of HCC-patients and healthy tissues were assessed for mRNA expression of 49 CTAs by RT-qPCR and protein expression of five CTAs by immunohistochemistry. Twelve CTA-mRNAs were expressed in ≥10% of HCC-tumors and not in healthy tissues except testis. In tumors, mRNA and protein of ≥ 1 CTA was expressed in 78% and 71% of HCC-patients, respectively. In TFL, CTA mRNA and protein was found in 45% and 30% of HCC-patients, respectively. Interestingly, CTA-expression in TFL was an independent negative prognostic factor for post-resection HCC-recurrence and survival. We established a panel of 12 testis-restricted CTAs expressed in tumors of most HCC-patients. The increased risk of HCC-recurrence in patients with CTA expression in TFL, suggests that CTA-expressing (pre-)malignant cells may be a source of HCC-recurrence, reflecting the relevance of targeting these to prevent HCC-recurrence.

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231 A novel discovery pipeline identifies melanoma-specific antibodies in patients responding to immune checkpoint inhibitors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0231 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A249-A249

Author(s):

Daniel Delitto ◽

Evan Lipson ◽

Laura Cappelli ◽

Klaus Busam ◽

Antony Rosen ◽

...

Keyword(s):

Metastatic Melanoma ◽

Treatment Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Specific Antibodies ◽

Cancer Testis Antigens ◽

Circulating Antibodies ◽

Cancer Testis

BackgroundTumor-specific antibodies have been reported in patients with cancers responding to immune checkpoint inhibitors (ICI), and there is an increasing appreciation for the potential role of B cells in mediating ICI responses. However, the humoral immune response to melanoma remains incompletely defined. We hypothesized that screening sera for antibodies by immunoprecipitation with lysates of cultured melanoma cells would increase the likelihood of detecting circulating antibodies in melanoma patients receiving ICI, and potentially identify novel antibody targets associated with treatment response and/or immune-related adverse events (IRAEs).MethodsPre-and on/post-treatment sera or plasma from 12 clinically-annotated patients with advanced metastatic melanoma receiving ICI were assayed for tumor-specific antibodies with an established immunoprecipitation platform. 35S-methionine-labeled lysates from cultured 624Mel cells were used for immunoprecipitation. 624Mel expresses several shared non-mutated melanoma antigens (e.g., MAGEA3, tyrosinase, MART-1/Melan-A, gp75, and gp100). Antigen identity was determined using on-bead digests followed by mass spectrometry, and was confirmed by immunoprecipitation with in vitro transcription/translation (IVTT) products.ResultsAntibodies reactive against 624Mel proteins were detected in 4 of 12 (33%) patients (table 1). Mass spectrometric sequencing performed on proteins captured with sera from 3 of 4 patients identified several putative antigens. Immunoprecipitation with IVTT candidate proteins confirmed antibodies against melanoma-associated and cancer testis antigens NY-ESO-1, SSX2 and MAGEA10. Antibodies were observed in 1 of 1 (100%) patient with a complete response, 2 of 4 (50%) with a partial response, 1 of 1 (100%) with stable disease, and 0 of 6 (0%) with progressive disease. Antibody levels varied over the course of therapy, with previously undetectable specificities arising during treatment response in patients #1–3. Patient #1 with a complete tumor regression developed antibodies to SSX2 and MAGEA10 that were absent before treatment. Further, detection of these antibodies coincided with diagnosis of IRAEs (anti-SSX2 with pancreatitis and anti-MAGEA10 with dermatitis). In contrast, patient #3, initially with a partial tumor regression, demonstrated a loss of detectable anti-NY-ESO-1 antibodies upon disease progression, and subsequent metastasectomy demonstrated loss of NY-ESO-1 protein expression in the progressing tumor. Testing sera from all 12 patients with IVTT products for NY-ESO-1, SSX2 and MAGEA10 did not reveal additional humoral responses.Abstract 231 Table 1Antibodies detected in the serum or plasma of patients with metastatic melanoma treated with ICI therapy. Treatment response indicates best overall response according to RECIST v1.1. Post-treatment blood collections were drawn during or after ICI therapy.ConclusionsOur comprehensive screening platform detected circulating antibodies specific to multiple melanoma-associated and cancer testis antigens in patients deriving clinical benefit from ICI. Expanded investigations of the evolution of antibody production over the course of ICI therapy, associated with tumor response to treatment and development of IRAEs, are warranted.AcknowledgementsThis study was supported by the Johns Hopkins Bloomberg-Kimmel Institute for Cancer Immunotherapy, and NIH P30-AR070254.Ethics ApprovalThis study was approved by the Johns Hopkins Institutional Review Board, approval #NA_00090257.

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