Background: Pancreatic
cancer is one of the most lethal types of cancer, and immunotherapy has become a
promising remedy with advancements in tumor immunology. However, predicting the
clinical response to immunotherapy in pancreatic cancer remains a dilemma for clinicians. Methods: GEPIA database was used to analyze
the differential expression of MMR and PD-L1 genes in 33 common cancer types including
pancreatic cancer. The expression levels of MMR and PD-L1 genes were downloaded
from the GEPIA and GEO databases to analyze the correlation between MMR genes and
PD-L1, and the clinicopathological and survival information were downloaded from
the TCGA databases to analyze the relationship between the expression of MMR, PD-L1
and？clinicopathological characteristics, prognosis.
Meanwhile, the tumor tissue samples of 41 patients with pancreatic cancer were collected,
and the protein expression levels of MMR and PD-L1 were
detected by immunohistochemical assay. Furthermore, we analyzed the correlation
between MMR and PD-L1, and the correlation between the expression of MMR, PD-L1
and clinicopathological characteristics, prognosis of pancreatic cancer patients. Results: Bioinformatics analysis showed that MLH1, MLH3, MSH2, MSH3, and
PMS2 were highly expressed in most cancer types including pancreatic cancer (P < 0.05). TCGA data revealed that MLH1 expression was related to gender (P = 0.012), clinical stage (I vs II: P = 0.016), MSH2
expression was related to clinical stage (P < 0.05), T stage (T3 vs
T4: P = 0.039), and MSH3 expression was related to T stage (P <
0.05). Besides, both MSH2 expression (P < 0.001) and MSH6 (P =
0.044) were significantly associated with prognosis. GEPIA data also showed that
MSH2 expression was related to prognosis (P = 0.008). The correlation analysis
revealed that the expressions MSH2, MLH1, PMS2 had strong correlations with PD-L1
both in GEPIA and GEO databases. Real-world data indicated that of the 41 pancreatic
cancer patients, 5 cases had MLH1 deletion, 5 cases had MSH2 deletion, 4 cases had
PMS2 deletion, and 12 cases had PD-L1 positive expression. Notably, PMS2 deletion
was associated with PD-L1 positive expression (P = 0.035). In addition, MLH1
was related to clinical stage (P = 0.033), age (P = 0.048), and MSH2
was related to clinical stage (P = 0.033). However, MLH1 (P = 0.697),
MSH2 (P = 0.956), PMS2
References
[1]
Xia, C., Dong, X., Li, H., Cao, M., Sun, D., He, S., Yang, F., Yan, X., Zhang, S., Li, N. and Chen, W. (2022) Cancer Statistics in China and United States, 2022: Profiles, Trends, and Determinants. Chinese Medical Journal, 135, 584-590.
https://doi.org/10.1097/CM9.0000000000002108
[2]
Rahib, L., Smith, B.D., Aizenberg, R., Rosenzweig, A.B., Fleshman, J.M. and Matrisian, L.M. (2014) Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Research, 74, 2913-2921. https://doi.org/10.1158/0008-5472.CAN-14-0155
[3]
Chen, H. and Hong, G. (2021) The Clinical Value of the Ratio of Neutrophils to Lymphocytes (NLR) and Prognostic Nutrition Index (PNI) in Evaluating the Prognosis of Patients with Advanced Pancreatic Cancer. Zhejiang Clinical Medical Journal, 23, 1163-1165, 1168.
[4]
Li, F., Li, Y., Gao, F., Qin, Y., Deng, Y., Tang, J., et al. (2021) Effect of Modified Yi Yan Xiao Formula Combined with Chemotherapy on Quality of Life and Survival Time in Patients with Advanced Pancreatic Cancer. Journal of Traditional Chinese Medicine, 62, 887-892.
[5]
Zhou, F., Chen, S., Sun, Y. and Tang, L. (2020) Prognostic Value of the Systemic Immune-Inflammation Index in Patients with Pancreatic Cancer: A Systematic Review and Meta-Analysis. Chinese Journal of General Surgery, No. 9, 1076-1083.
https://doi.org/10.21203/rs.3.rs-70837/v1
[6]
Garris, C.S., Arlauckas, S.P., Kohler, R.H., Trefny, M.P., Garren, S., Piot, C., Engblom, C., Pfirschke, C., Siwicki, M., Gungabeesoon, J., Freeman, G.J., Warren, S.E., Ong, S., Browning, E., Twitty, C.G., Pierce, R.H., Le, M.H., Algazi, A.P., Daud, A.I., Pai, S.I. and Pittet, M.J. (2018) Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12. Immunity, 49, 1148-1161.e7. https://doi.org/10.1016/j.immuni.2018.09.024
[7]
Li, J., Yun, T., Gao, S., Liu, X., Pu, N., Li, C., et al. (2018) Prognostic Analysis of PD-L1 Expression in Patients with Resectable Pancreatic Adenocarcinoma. Fudan University Journal of Medical Sciences, 45, 788-792.
[8]
Ott, P.A., Bang, Y.J., Piha-Paul, S.A., Razak, A.R.A., Bennouna, J., Soria, J.C., Rugo, H.S., Cohen, R.B., O’Neil, B.H., Mehnert, J.M., Lopez, J., Doi, T., van Brummelen, E.M.J., Cristescu, R., Yang, P., Emancipator, K., Stein, K., Ayers, M., Joe, A.K. and Lunceford, J.K. (2019) T-Cell-Inflamed Gene-Expression Profile, Programmed Death Ligand 1 Expression, and Tumor Mutational Burden Predict Efficacy in Patients Treated with Pembrolizumab across 20 Cancers: KEYNOTE-028. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 37, 318-327. https://doi.org/10.1200/JCO.2018.78.2276
[9]
Eto, S., Yoshikawa, K., Nishi, M., Higashijima, J., Tokunaga, T., Nakao, T., Kashihara, H., Takasu, C., Iwata, T. and Shimada, M. (2016) Programmed Cell Death Protein 1 Expression Is an Independent Prognostic Factor in Gastric Cancer after Curative Resection. Gastric Cancer: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 19, 466-471.
https://doi.org/10.1007/s10120-015-0519-7
[10]
Koessler, T., Oestergaard, M.Z., Song, H., Tyrer, J., Perkins, B., Dunning, A.M., Easton, D.F. and Pharoah, P.D. (2008) Common Variants in Mismatch Repair Genes and Risk of Colorectal Cancer. Gut, 57, 1097-1101.
https://doi.org/10.1136/gut.2007.137265
[11]
Llosa, N.J., Cruise, M., Tam, A., Wicks, E.C., Hechenbleikner, E.M., Taube, J.M., Blosser, R.L., Fan, H., Wang, H., Luber, B.S., Zhang, M., Papadopoulos, N., Kinzler, K.W., Vogelstein, B., Sears, C.L. anders, R.A., Pardoll, D.M. and Housseau, F. (2015) The Vigorous Immune Microenvironment of Microsatellite Instable Colon Cancer Is Balanced by Multiple Counter-Inhibitory Checkpoints. Cancer Discovery, 5, 43-51. https://doi.org/10.1158/2159-8290.CD-14-0863
[12]
Xv, R., Shen, L., Li, J. (2019) The Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the Diagnosis and Treatment of Gastric Cancer. The Peoples Medical Publishing House, Beijing, 143-145.
[13]
Gao, H.L., Liu, L., Qi, Z.H., Xu, H.X., Wang, W.Q., Wu, C.T., Zhang, S. R., Xu, J.Z., Ni, Q.X. and Yu, X.J. (2018) The Clinicopathological and Prognostic Significance of PD-L1 Expression in Pancreatic Cancer: A Meta-Analysis. Hepatobiliary & Pancreatic Diseases International: HBPD INT, 17, 95-100.
https://doi.org/10.1016/j.hbpd.2018.03.007
[14]
Sharma, P. and Allison, J.P. (2015) Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential. Cell, 161, 205-214.
https://doi.org/10.1016/j.cell.2015.03.030
[15]
Hanahan, D. and Weinberg, R.A. (2011) Hallmarks of Cancer: The Next Generation. Cell, 144, 646-674. https://doi.org/10.1016/j.cell.2011.02.013
[16]
Luchini, C., Bibeau, F., Ligtenberg, M.J.L., Singh, N., Nottegar, A., Bosse, T., Miller, R., Riaz, N., Douillard, J.Y. andre, F. and Scarpa, A. (2019) ESMO Recommendations on Microsatellite Instability Testing for Immunotherapy in Cancer, and Its Relationship with PD-1/PD-L1 Expression and Tumour Mutational Burden: A Systematic Review-Based Approach. Annals of Oncology: Official Journal of the European Society for Medical Oncology, 30, 1232-1243.
https://doi.org/10.1093/annonc/mdz116
[17]
Kim, S.T., Klempner, S.J., Park, S.H., Park, J.O., Park, Y.S., Lim, H.Y., Kang, W.K., Kim, K.M. and Lee, J. (2017) Correlating Programmed Death Ligand 1 (PD-L1) Expression, Mismatch Repair Deficiency, and Outcomes across Tumor Types: Implications for Immunotherapy. Oncotarget, 8, 77415-77423.
https://doi.org/10.18632/oncotarget.20492
[18]
Svensson, M.C., Borg, D., Zhang, C., Hedner, C., Nodin, B., Uhlén, M., Mardinoglu, A., Leandersson, K. and Jirström, K. (2019) Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship with Mismatch Repair Status and Survival. Frontiers in Oncology, 9, 136.
https://doi.org/10.3389/fonc.2019.00136
[19]
Le, D.T., Uram, J.N., Wang, H., Bartlett, B.R., Kemberling, H., Eyring, A.D., Skora, A.D., Luber, B.S., Azad, N.S., Laheru, D., Biedrzycki, B., Donehower, R.C., Zaheer, A., Fisher, G.A., Crocenzi, T.S., Lee, J.J., Duffy, S.M., Goldberg, R.M., de la Chapelle, A., Koshiji, M. and Diaz, L.A. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. The New England Journal of Medicine, 372, 2509-2520.
https://doi.org/10.1056/NEJMoa1500596
[20]
Lee, V., Murphy, A., Le, D.T. and Diaz, L.A. (2016) Mismatch Repair Deficiency and Response to Immune Checkpoint Blockade. The Oncologist, 21, 1200-1211.
https://doi.org/10.1634/theoncologist.2016-0046
[21]
Ma, W., Gilligan, B.M., Yuan, J. and Li, T. (2016) Current Status and Perspectives in Translational Biomarker Research for PD-1/PD-L1 Immune Checkpoint Blockade Therapy. Journal of Hematology & Oncology, 9, 47.
https://doi.org/10.1186/s13045-016-0277-y
[22]
Böger, C., Behrens, H.M., Mathiak, M., Krüger, S., Kalthoff, H. and Röcken, C. (2016) PD-L1 Is an Independent Prognostic Predictor in Gastric Cancer of Western Patients. Oncotarget, 7, 24269-24283. https://doi.org/10.18632/oncotarget.8169
[23]
Saif, H., Kumar, K., Mufti, S.S., Giri, R., Hrishi, V., Sarathy, V., et al. (2020) Correlation of Programmed Death Ligand-1 (PD-L1) Expression with Clinicopathological Features in Non-Small Cell Lung Carcinoma: Experience from a Tertiary Cancer Care center in India. Journal of Cancer Therapy, 11, 172-187.
https://doi.org/10.4236/jct.2020.113015
[24]
Wang, Q., Liu, F. and Liu, L. (2017) Prognostic Significance of PD-L1 in Solid Tumor: An Updated Meta-Analysis. Medicine, 96, e6369.
https://doi.org/10.1097/MD.0000000000006369
[25]
Birnbaum, D.J., Finetti, P., Lopresti, A., Gilabert, M., Poizat, F., Turrini, O., Raoul, J.L., Delpero, J.R., Moutardier, V., Birnbaum, D., Mamessier, E. and Bertucci, F. (2016) Prognostic Value of PDL1 Expression in Pancreatic Cancer. Oncotarget, 7, 71198-71210. https://doi.org/10.18632/oncotarget.11685
[26]
Guo, Y., Wu, Y., Huang, J., Lu, X. and Chen, X. (2019) Expression of PD-L1 and Its Clinicopathological Significance in Pancreatic Ductal Carcinoma. Journal of Clinical and Experimental Pathology, 35, 1177-1180.
[27]
Tomaszewska, R., Okoń, K. and Stachura, J. (2003) Expression of the DNA Mismatch Repair Proteins (hMLH1 and hMSH2) in Infiltrating Pancreatic Cancer and Its Relation to Some Phenotypic Features. Polish Journal of Pathology: Official Journal of the Polish Society of Pathologists, 54, 31-37.
[28]
Riazy, M., Kalloger, S.E., Sheffield, B.S., Peixoto, R.D., Li-Chang, H.H., Scudamore, C.H., Renouf, D.J. and Schaeffer, D.F. (2015) Mismatch Repair Status May Predict Response to Adjuvant Chemotherapy in Resectable Pancreatic Ductal Adenocarcinoma. Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc, 28, 1383-1389.
https://doi.org/10.1038/modpathol.2015.89
[29]
Eatrides, J.M., Coppola, D., Al Diffalha, S., et al. (2016) Microsatellite Instability in Pancreatic Cancer. Journal of Clinical Oncology, 34, e15753.
https://doi.org/10.1200/JCO.2016.34.15_suppl.e15753
[30]
Chen, P., Wang, W., Li, G., Li, H., Hang, X. and Liu, H. (2018) Expression of hMLH1, hMSH2 and hMSH6 in Young and Middle-Aged Patients with Sporadic Gastric Cancer and Its Effect on Prognosis. Journal of Lanzhou University Medical Sciences, No. 4, 40-45.
[31]
Jin, W., Ma, Y., Wang, Y. and Liu, A. (2018) Expression of Mismatch Repair Proteins (MLH1, MSH2, MSH6 and PMS2) in Endometrial Cancer and Their Clinical Significance. Chinese Journal of Diagnostic Pathology, No. 5, 335-339.
[32]
Yoo, K.H., Won, K.Y., Lim, S.J., Park, Y.K. and Chang, S.G. (2014) Deficiency of MSH2 Expression Is Associated with Clear Cell Renal Cell Carcinoma. Oncology Letters, 8, 2135-2139. https://doi.org/10.3892/ol.2014.2482
