Skip to main content
construction release_alert
Scholars@Duke will be undergoing maintenance April 11-15. Some features may be unavailable during this time.
cancel

Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer.

Publication ,  Journal Article
Strickland, KC; Howitt, BE; Shukla, SA; Rodig, S; Ritterhouse, LL; Liu, JF; Garber, JE; Chowdhury, D; Wu, CJ; D'Andrea, AD; Matulonis, UA ...
Published in: Oncotarget
March 22, 2016

Immune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumor-specific neoantigens, and, therefore, exhibit increased TILs and PD-1/PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

March 22, 2016

Volume

7

Issue

12

Start / End Page

13587 / 13598

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Survival Rate
  • Programmed Cell Death 1 Receptor
  • Prognosis
  • Ovarian Neoplasms
  • Neoplasm Staging
  • Neoplasm Grading
  • Mutation
  • Lymphocytes, Tumor-Infiltrating
  • Humans
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Strickland, K. C., Howitt, B. E., Shukla, S. A., Rodig, S., Ritterhouse, L. L., Liu, J. F., … Konstantinopoulos, P. A. (2016). Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget, 7(12), 13587–13598. https://doi.org/10.18632/oncotarget.7277
Strickland, Kyle C., Brooke E. Howitt, Sachet A. Shukla, Scott Rodig, Lauren L. Ritterhouse, Joyce F. Liu, Judy E. Garber, et al. “Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer.Oncotarget 7, no. 12 (March 22, 2016): 13587–98. https://doi.org/10.18632/oncotarget.7277.
Strickland KC, Howitt BE, Shukla SA, Rodig S, Ritterhouse LL, Liu JF, Garber JE, Chowdhury D, Wu CJ, D’Andrea AD, Matulonis UA, Konstantinopoulos PA. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget. 2016 Mar 22;7(12):13587–13598.

Published In

Oncotarget

DOI

EISSN

1949-2553

Publication Date

March 22, 2016

Volume

7

Issue

12

Start / End Page

13587 / 13598

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Survival Rate
  • Programmed Cell Death 1 Receptor
  • Prognosis
  • Ovarian Neoplasms
  • Neoplasm Staging
  • Neoplasm Grading
  • Mutation
  • Lymphocytes, Tumor-Infiltrating
  • Humans