Chemotherapy shifts the balance in favor of cd8+ tnfr2+ tils in triple-negative breast tumors

Tamir Baram, Nofar Erlichman, Maya Dadiani, Nora Balint-Lahat, Anya Pavlovski, Tsipi Meshel, Dana Morzaev-Sulzbach, Einav Nili Gal-Yam, Iris Barshack, Adit Ben-Baruch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Triple-negative breast cancer (TNBC) is primarily treated via chemotherapy; in parallel, efforts are made to introduce immunotherapies into TNBC treatment. CD4+ TNFR2+ lymphocytes were reported as Tregs that contribute to tumor progression. However, our published study indicated that TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs) were associated with improved survival in TNBC patient tumors. Based on our analyses of the contents of CD4+ and CD8+ TILs in TNBC patient tumors, in the current study, we determined the impact of chemotherapy on CD4+ and CD8+ TIL subsets in TNBC mouse tumors. We found that chemotherapy led to (1) a reduction in CD4+ TNFR2+ FOXP3+ TILs, indicating that chemotherapy decreased the content of CD4+ TNFR2+ Tregs, and (2) an elevation in CD8+ TNFR2+ and CD8+ TNFR2+ PD-1+ TILs; high levels of these two subsets were significantly associated with reduced tumor growth. In spleens of tumor-bearing mice, chemotherapy down-regulated CD4+ TNFR2+ FOXP3+ cells but the subset of CD8+ TNFR2+ PD-1+ was not present prior to chemotherapy and was not increased by the treatment. Thus, our data suggest that chemotherapy promotes the proportion of protective CD8+ TNFR2+ TILs and that, unlike other cancer types, therapeutic strategies directed against TNFR2 may be detrimental in TNBC.

Original languageEnglish
Article number1429
Issue number6
StatePublished - Jun 2021


  • CD4+ lymphocytes
  • CD8+ lymphocytes
  • Forkhead box P3 (FOXP3)
  • Programmed cell death protein 1 (PD-1)
  • Splenocytes
  • Triple-negative breast cancer (TNBC)
  • Tumor necrosis factor receptor 2 (TNFR2)
  • Tumor necrosis factor α (TNFα)
  • Tumor-infiltrating lymphocytes (TILs)


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