Expression of PD-1 in Tumor Cells is Associated with Shorter Survival in Non-metastatic Intestinal-type Gastric Adenocarcinoma
Abstract
There is an urgent need to discover novel prognostic biomarkers and treatment strategies for gastric cancer (GC) patients. Several immune-related markers have been proposed as prognostic tools and immunotherapeutic targets to manage diseases. In this regard, we evaluated the expression pattern and prognostic significance of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), CD45RO+ tumor-infiltrating lymphocytes (TILs), and DNA mismatch repair (MMR) proteins (MLH1, MSH2, PMS2, and MSH6) in non-metastatic intestinal-type gastric adenocarcinoma.
Samples and data from 70 GC patients were collected. Immunohistochemistry staining was used to detect the markers. We then evaluated the prognosis significance of each marker and their intercorrelation.
Cytoplasmic PD-1 expressed by tumor cells was significantly associated with poorer survival. However, multivariate analysis indicated stronger prognostic values for TNM stage, tumor location, and extracellular mucin. A significant positive association was found between CD45ROhigh TILs and PD-1 expression on tumor-infiltrating cells (TICs). All GC patients with deficient MMR (d‑MMR) had a higher number of CD45RO+ TILs and were associated with PD-1+ TICs and PD‑L1+ tumor cells (TCs). However, the difference was not statistically significant.
Despite the association of PD‑1 overexpression on TCs with shorter overall survival, histopathological factors, including tumor location, TNM stage, and extracellular mucin, remain the most decisive prognostic factors in non-metastatic intestinal-type gastric adenocarcinoma. Additionally, our data support a prognostic role for d-MMR and CD45RO, but not PD-1 and PD-L1 expression on TICs.
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2. Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.
3. Thrift AP, El-Serag HB. Burden of Gastric Cancer. Clin Gastroenterol Hepatol. 2020;18(3):534-42.
4. He Y, Song H, Jiang Y, Ren W. Identification of Immune-Related Prognostic Markers in Gastric Cancer. J Healthc Eng. 2022;2022:7897274.
5. Trabelsi M, Farah F, Zouari B, Jaafoura MH, Kharrat M. An Immunoscore System Based On CD3(+) And CD8(+) Infiltrating Lymphocytes Densities To Predict The Outcome Of Patients With Colorectal Adenocarcinoma. Onco Targets Ther. 2019;12:8663-73.
6. Voutsadakis IA. A Systematic Review and Meta-analysis of PD-1 and PD-L1 Inhibitors Monotherapy in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma. Euroasian J Hepatogastroenterol. 2020;10(2):56-63.
7. Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-86.
8. Ren Q, Zhu P, Zhang H, Ye T, Liu D, Gong Z, et al. Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer. Cancer Cell Int. 2020;20:92.
9. Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker. Cancer cell. 2021;39(2):154-73.
10. Pećina-Šlaus N, Kafka A, Salamon I, Bukovac A. Mismatch Repair Pathway, Genome Stability and Cancer. Front Mol Biosci. 2020;7:122-8.
11. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10.
12. Malka D, Lièvre A, André T, Taïeb J, Ducreux M, Bibeau F. Immune scores in colorectal cancer: Where are we? Eur J Cancer. 2020;140(12):105-18.
13. Rauser S, Langer R, Tschernitz S, Gais P, Jütting U, Feith M, et al. High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma. BMC cancer. 2010;10:608.
14. Hu G, Wang S. Tumor-infiltrating CD45RO(+) Memory T Lymphocytes Predict Favorable Clinical Outcome in Solid Tumors. Sci Rep. 2017;7(1):10376-8.
15. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-9.
16. Wang YL, Gong Y, Lv Z, Li L, Yuan Y. Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment. J Cancer. 2021;12(6):1698-707.
17. Sharma M, Yang Z, Miyamoto H. Immunohistochemistry of immune checkpoint markers PD-1 and PD-L1 in prostate cancer. Medicine (Baltimore). 2019;98(38):e17257.
18. van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, van Houdt L, Gorris MAJ, van Dam LS, et al. Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8(+) lymphocytes in primary sarcomas is subtype dependent. Oncotarget. 2017;8(41):71371-84.
19. Wakatsuki K, Sho M, Yamato I, Takayama T, Matsumoto S, Tanaka T, et al. Clinical impact of tumor-infiltrating CD45RO⁺ memory T cells on human gastric cancer. Oncol Rep. 2013;29(5):1756-62.
20. McCarthy AJ, Capo-Chichi J-M, Spence T, Grenier S, Stockley T, Kamel-Reid S, et al. Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation. J Pathol Clin Res. 2019;5(2):115-29.
21. Fang W, Chen Y, Sheng J, Zhou T, Zhang Y, Zhan J, et al. Association between PD-L1 Expression on Tumour-Infiltrating Lymphocytes and Overall Survival in Patients with Gastric Cancer. J Cancer. 2017;8(9):1579-85.
22. Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, et al. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget. 2016;7(2):1486-99.
23. Ichikawa J, Yoshida T, Isser A, Laino AS, Vassallo M, Woods D, et al. Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells. Clin Cancer Res. 2020;26(13):3384-96.
24. Hwang HS, Kim D, Choi J. Distinct mutational profile and immune microenvironment in microsatellite-unstable and POLE-mutated tumors. J Immunother Cancer. 2021;9(10):e002797.
25. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6):1242-56.
26. Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, et al. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology. 2017;66(6):1920-33.
27. D'Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95-102.
28. Machado I, López-Guerrero JA, Scotlandi K, Picci P, Llombart-Bosch A. Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT). Virchows Arch. 2018;472(5):815-24.
29. Cai L, Sun Y, Wang K, Guan W, Yue J, Li J, et al. The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer. Front Oncol. 2020;10:1269.
30. Conforti F, Pala L, Pagan E, Corti C, Bagnardi V, Queirolo P, et al. Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials. ESMO open. 2021;6(5):100251.
31. Wu Y, Ju Q, Jia K, Yu J, Shi H, Wu H, et al. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). Int J Cancer. 2018;143(1):45-51.
32. Angell HK, Lee J, Kim KM, Kim K, Kim ST, Park SH, et al. PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology. 2019;8(2):e1544442.
33. Svensson MC, Borg D, Zhang C, Hedner C, Nodin B, Uhlén M, et al. Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival. Front Oncol. 2019;9:136.
34. Zhou C, Li J, Wu Y, Diao P, Yang J, Cheng J. High Density of Intratumor CD45RO(+) Memory Tumor-Infiltrating Lymphocytes Predicts Favorable Prognosis in Patients With Oral Squamous Cell Carcinoma. J Oral Maxillofac Surg. 2019;77(3):536-45.
35. Hang J, Huang J, Zhou S, Wu L, Zhu Y, Zhu L, et al. The clinical implication of CD45RA(+) naïve T cells and CD45RO(+) memory T cells in advanced pancreatic cancer: a proxy for tumor biology and outcome prediction. Cancer Med. 2019;8(3):1326-35.
36. Koike K, Nishiyama K, Dehari H, Ogi K, Sasaki T, Shimizu S, et al. Prognostic Value of CD45Ro(+) T-Cell Expression in Patients With Oral Squamous Cell Carcinoma. Anticancer Res. 2021;41(9):4515-22.
37. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer. 2008;99(10):1704-11.
38. Pauken KE, Godec J, Odorizzi PM, Brown KE, Yates KB, Ngiow SF, et al. The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection. Cell Rep. 2020;31(13):107827.
39. Davidson TB, Lee A, Hsu M, Sedighim S, Orpilla J, Treger J, et al. Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation. Clinical cancer research : an official journal of the American Association for Clin Cancer Res. 2019;25(6):1913-22.
40. Tsai C-Y, Lin T-A, Huang S-C, Hsu J-T, Yeh C-N, Chen T-C, et al. Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched. Oncologist. 2020;25(7):e1021-e30.
41. Wei S, Lu J, Lou J, Shi C, Mo S, Shao Y, et al. Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration. Front Genet. 2020;11:663.
42. Lizardo DY, Kuang C, Hao S, Yu J, Huang Y, Zhang L. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside. Biochim Biophys Acta Rev Cancer. 2020;1874(2):188447.
43. Wen F, Ruan S, Huang W, Chen X, Wang Y, Gu S, et al. Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma. Front Med (Lausanne). 2021;8(2):5-9.
44. Jin S, Xu B, Yu L, Fu Y, Wu H, Fan X, et al. The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy. Oncotarget. 2017;8(24):38850-62.
45. Sun Y, Yu W, Guan W, Cai L, Qiao M, Zheng L, et al. Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer. Cancer Manage Res. 2019;11:6397-410.
46. Wang L, Zhang Q, Ni S, Tan C, Cai X, Huang D, et al. Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status. Cancer Med. 2018;7(6):2612-20.
47. Shin S-J, Kim SY, Choi YY, Son T, Cheong J-H, Hyung WJ, et al. Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response. Oncologist. 2019;24(9):e835-e44.
48. Tsai CY, Lin TA, Huang SC, Hsu JT, Yeh CN, Chen TC, et al. Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched. Oncologist. 2020;25(7):e1021-e30.
49. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018;4(5):e180013-e.
50. Shitara K, Van Cutsem E, Bang Y-J, Fuchs C, Wyrwicz L, Lee K-W, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6(10):1571-80.
51. Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, et al. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018;36(28):2836-44.
52. Pietrantonio F, Randon G, Di Bartolomeo M, Luciani A, Chao J, Smyth EC, et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO open. 2021;6(1):100036.
53. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New En J Med. 2022;386(25):2363-76.
2. Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A. Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol. 2012;3(3):251-61.
3. Thrift AP, El-Serag HB. Burden of Gastric Cancer. Clin Gastroenterol Hepatol. 2020;18(3):534-42.
4. He Y, Song H, Jiang Y, Ren W. Identification of Immune-Related Prognostic Markers in Gastric Cancer. J Healthc Eng. 2022;2022:7897274.
5. Trabelsi M, Farah F, Zouari B, Jaafoura MH, Kharrat M. An Immunoscore System Based On CD3(+) And CD8(+) Infiltrating Lymphocytes Densities To Predict The Outcome Of Patients With Colorectal Adenocarcinoma. Onco Targets Ther. 2019;12:8663-73.
6. Voutsadakis IA. A Systematic Review and Meta-analysis of PD-1 and PD-L1 Inhibitors Monotherapy in Metastatic Gastric and Gastroesophageal Junction Adenocarcinoma. Euroasian J Hepatogastroenterol. 2020;10(2):56-63.
7. Wei SC, Duffy CR, Allison JP. Fundamental Mechanisms of Immune Checkpoint Blockade Therapy. Cancer Discov. 2018;8(9):1069-86.
8. Ren Q, Zhu P, Zhang H, Ye T, Liu D, Gong Z, et al. Identification and validation of stromal-tumor microenvironment-based subtypes tightly associated with PD-1/PD-L1 immunotherapy and outcomes in patients with gastric cancer. Cancer Cell Int. 2020;20:92.
9. Jardim DL, Goodman A, de Melo Gagliato D, Kurzrock R. The Challenges of Tumor Mutational Burden as an Immunotherapy Biomarker. Cancer cell. 2021;39(2):154-73.
10. Pećina-Šlaus N, Kafka A, Salamon I, Bukovac A. Mismatch Repair Pathway, Genome Stability and Cancer. Front Mol Biosci. 2020;7:122-8.
11. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2020;38(1):1-10.
12. Malka D, Lièvre A, André T, Taïeb J, Ducreux M, Bibeau F. Immune scores in colorectal cancer: Where are we? Eur J Cancer. 2020;140(12):105-18.
13. Rauser S, Langer R, Tschernitz S, Gais P, Jütting U, Feith M, et al. High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma. BMC cancer. 2010;10:608.
14. Hu G, Wang S. Tumor-infiltrating CD45RO(+) Memory T Lymphocytes Predict Favorable Clinical Outcome in Solid Tumors. Sci Rep. 2017;7(1):10376-8.
15. Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, et al. The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-9.
16. Wang YL, Gong Y, Lv Z, Li L, Yuan Y. Expression of PD1/PDL1 in gastric cancer at different microsatellite status and its correlation with infiltrating immune cells in the tumor microenvironment. J Cancer. 2021;12(6):1698-707.
17. Sharma M, Yang Z, Miyamoto H. Immunohistochemistry of immune checkpoint markers PD-1 and PD-L1 in prostate cancer. Medicine (Baltimore). 2019;98(38):e17257.
18. van Erp AEM, Versleijen-Jonkers YMH, Hillebrandt-Roeffen MHS, van Houdt L, Gorris MAJ, van Dam LS, et al. Expression and clinical association of programmed cell death-1, programmed death-ligand-1 and CD8(+) lymphocytes in primary sarcomas is subtype dependent. Oncotarget. 2017;8(41):71371-84.
19. Wakatsuki K, Sho M, Yamato I, Takayama T, Matsumoto S, Tanaka T, et al. Clinical impact of tumor-infiltrating CD45RO⁺ memory T cells on human gastric cancer. Oncol Rep. 2013;29(5):1756-62.
20. McCarthy AJ, Capo-Chichi J-M, Spence T, Grenier S, Stockley T, Kamel-Reid S, et al. Heterogenous loss of mismatch repair (MMR) protein expression: a challenge for immunohistochemical interpretation and microsatellite instability (MSI) evaluation. J Pathol Clin Res. 2019;5(2):115-29.
21. Fang W, Chen Y, Sheng J, Zhou T, Zhang Y, Zhan J, et al. Association between PD-L1 Expression on Tumour-Infiltrating Lymphocytes and Overall Survival in Patients with Gastric Cancer. J Cancer. 2017;8(9):1579-85.
22. Darb-Esfahani S, Kunze CA, Kulbe H, Sehouli J, Wienert S, Lindner J, et al. Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma. Oncotarget. 2016;7(2):1486-99.
23. Ichikawa J, Yoshida T, Isser A, Laino AS, Vassallo M, Woods D, et al. Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells. Clin Cancer Res. 2020;26(13):3384-96.
24. Hwang HS, Kim D, Choi J. Distinct mutational profile and immune microenvironment in microsatellite-unstable and POLE-mutated tumors. J Immunother Cancer. 2021;9(10):e002797.
25. Kleffel S, Posch C, Barthel SR, Mueller H, Schlapbach C, Guenova E, et al. Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth. Cell. 2015;162(6):1242-56.
26. Li H, Li X, Liu S, Guo L, Zhang B, Zhang J, et al. Programmed cell death-1 (PD-1) checkpoint blockade in combination with a mammalian target of rapamycin inhibitor restrains hepatocellular carcinoma growth induced by hepatoma cell-intrinsic PD-1. Hepatology. 2017;66(6):1920-33.
27. D'Incecco A, Andreozzi M, Ludovini V, Rossi E, Capodanno A, Landi L, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95-102.
28. Machado I, López-Guerrero JA, Scotlandi K, Picci P, Llombart-Bosch A. Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing's sarcoma family of tumors (ESFT). Virchows Arch. 2018;472(5):815-24.
29. Cai L, Sun Y, Wang K, Guan W, Yue J, Li J, et al. The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer. Front Oncol. 2020;10:1269.
30. Conforti F, Pala L, Pagan E, Corti C, Bagnardi V, Queirolo P, et al. Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials. ESMO open. 2021;6(5):100251.
31. Wu Y, Ju Q, Jia K, Yu J, Shi H, Wu H, et al. Correlation between sex and efficacy of immune checkpoint inhibitors (PD-1 and CTLA-4 inhibitors). Int J Cancer. 2018;143(1):45-51.
32. Angell HK, Lee J, Kim KM, Kim K, Kim ST, Park SH, et al. PD-L1 and immune infiltrates are differentially expressed in distinct subgroups of gastric cancer. Oncoimmunology. 2019;8(2):e1544442.
33. Svensson MC, Borg D, Zhang C, Hedner C, Nodin B, Uhlén M, et al. Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival. Front Oncol. 2019;9:136.
34. Zhou C, Li J, Wu Y, Diao P, Yang J, Cheng J. High Density of Intratumor CD45RO(+) Memory Tumor-Infiltrating Lymphocytes Predicts Favorable Prognosis in Patients With Oral Squamous Cell Carcinoma. J Oral Maxillofac Surg. 2019;77(3):536-45.
35. Hang J, Huang J, Zhou S, Wu L, Zhu Y, Zhu L, et al. The clinical implication of CD45RA(+) naïve T cells and CD45RO(+) memory T cells in advanced pancreatic cancer: a proxy for tumor biology and outcome prediction. Cancer Med. 2019;8(3):1326-35.
36. Koike K, Nishiyama K, Dehari H, Ogi K, Sasaki T, Shimizu S, et al. Prognostic Value of CD45Ro(+) T-Cell Expression in Patients With Oral Squamous Cell Carcinoma. Anticancer Res. 2021;41(9):4515-22.
37. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer. 2008;99(10):1704-11.
38. Pauken KE, Godec J, Odorizzi PM, Brown KE, Yates KB, Ngiow SF, et al. The PD-1 Pathway Regulates Development and Function of Memory CD8+ T Cells following Respiratory Viral Infection. Cell Rep. 2020;31(13):107827.
39. Davidson TB, Lee A, Hsu M, Sedighim S, Orpilla J, Treger J, et al. Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation. Clinical cancer research : an official journal of the American Association for Clin Cancer Res. 2019;25(6):1913-22.
40. Tsai C-Y, Lin T-A, Huang S-C, Hsu J-T, Yeh C-N, Chen T-C, et al. Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched. Oncologist. 2020;25(7):e1021-e30.
41. Wei S, Lu J, Lou J, Shi C, Mo S, Shao Y, et al. Gastric Cancer Tumor Microenvironment Characterization Reveals Stromal-Related Gene Signatures Associated With Macrophage Infiltration. Front Genet. 2020;11:663.
42. Lizardo DY, Kuang C, Hao S, Yu J, Huang Y, Zhang L. Immunotherapy efficacy on mismatch repair-deficient colorectal cancer: From bench to bedside. Biochim Biophys Acta Rev Cancer. 2020;1874(2):188447.
43. Wen F, Ruan S, Huang W, Chen X, Wang Y, Gu S, et al. Prognostic Value of Tumor Mutational Burden Related to Immune Infiltration in Cervical Squamous Cell Carcinoma. Front Med (Lausanne). 2021;8(2):5-9.
44. Jin S, Xu B, Yu L, Fu Y, Wu H, Fan X, et al. The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy. Oncotarget. 2017;8(24):38850-62.
45. Sun Y, Yu W, Guan W, Cai L, Qiao M, Zheng L, et al. Integrated assessment of PD-L1 expression and molecular classification facilitates therapy selection and prognosis prediction in gastric cancer. Cancer Manage Res. 2019;11:6397-410.
46. Wang L, Zhang Q, Ni S, Tan C, Cai X, Huang D, et al. Programmed death-ligand 1 expression in gastric cancer: correlation with mismatch repair deficiency and HER2-negative status. Cancer Med. 2018;7(6):2612-20.
47. Shin S-J, Kim SY, Choi YY, Son T, Cheong J-H, Hyung WJ, et al. Mismatch Repair Status of Gastric Cancer and Its Association with the Local and Systemic Immune Response. Oncologist. 2019;24(9):e835-e44.
48. Tsai CY, Lin TA, Huang SC, Hsu JT, Yeh CN, Chen TC, et al. Is Adjuvant Chemotherapy Necessary for Patients with Deficient Mismatch Repair Gastric Cancer?-Autophagy Inhibition Matches the Mismatched. Oncologist. 2020;25(7):e1021-e30.
49. Fuchs CS, Doi T, Jang RW, Muro K, Satoh T, Machado M, et al. Safety and Efficacy of Pembrolizumab Monotherapy in Patients With Previously Treated Advanced Gastric and Gastroesophageal Junction Cancer: Phase 2 Clinical KEYNOTE-059 Trial. JAMA Oncol. 2018;4(5):e180013-e.
50. Shitara K, Van Cutsem E, Bang Y-J, Fuchs C, Wyrwicz L, Lee K-W, et al. Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020;6(10):1571-80.
51. Janjigian YY, Bendell J, Calvo E, Kim JW, Ascierto PA, Sharma P, et al. CheckMate-032 Study: Efficacy and Safety of Nivolumab and Nivolumab Plus Ipilimumab in Patients With Metastatic Esophagogastric Cancer. J Clin Oncol. 2018;36(28):2836-44.
52. Pietrantonio F, Randon G, Di Bartolomeo M, Luciani A, Chao J, Smyth EC, et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO open. 2021;6(1):100036.
53. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New En J Med. 2022;386(25):2363-76.
| Files | ||
| Issue | Vol 21 No 6 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i6.11519 | |
| Keywords | ||
| Immunohistochemistry CD45RO antigens DNA mismatch repair PD-L1 PD-1 Stomach neoplasms | ||
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How to Cite
1.
Namvar N, Montazer M, Ahmadvand S, Sadeghian B, Ghaderi A. Expression of PD-1 in Tumor Cells is Associated with Shorter Survival in Non-metastatic Intestinal-type Gastric Adenocarcinoma. Iran J Allergy Asthma Immunol. 2022;21(6):600-615.
