TNFR2+ TILs are significantly associated with improved survival in triple-negative breast cancer patients

Maya Dadiani, Daniela Necula, Smadar Kahana-Edwin, Nino Oren, Tamir Baram, Irina Marin, Dana Morzaev-Sulzbach, Anya Pavlovski, Nora Balint-Lahat, Liat Anafi, Stefan Wiemann, Cindy Korner, Einav Nili Gal-Yam, Camila Avivi, Bella Kaufman, Iris Barshack, Adit Ben-Baruch*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


In view of the relatively limited efficacy of immunotherapies targeting the PD-1–PD-L1 axis in triple-negative breast cancer (TNBC) and of published reports on tumor-promoting roles of TNFR2+ tumor-infiltrating lymphocytes (TNFR2+ TILs), we determined the incidence of TNFR2+ TILs in TNBC patient tumors, their association with disease outcome and relations with PD-1+ TILs. Using a cohort of treatment-naïve TNBC patients with long follow-up (n = 70), we determined the presence of TNFR2+ TILs and PD-1+ TILs by immunohistochemistry. TILs (≥ 1% of cellular mass) and TNFR2+ TILs (≥ 1% of total TILs) were detected in 96% and 74% of tumors, respectively. The presence of TILs at > 5% of tumor cell mass (“Positive TILs”), as well as of positive TNFR2+ TILs (> 5%), was independently associated with good prognosis, and combination of both parameters demonstrated superior outcome relative to their lower levels. PD1+ TILs (> 5/hot spot) were detected in 63% of patients. High levels of PD-1+ TILs (> 20/hot spot) showed an unfavorable disease outcome, and in their presence, the favorable outcome of positive TNFR2+ TILs was ablated. Thus, TNFR2+ TILs are strongly connected to improved prognosis in TNBC; these findings suggest that TNFR2+ TILs have favorable effects in TNBC patients, unlike the tumor-promoting roles attributed to them in other cancer systems. Overall, our observations propose that the TNFR2+ TIL subset should not be targeted in the course of TNBC therapy; rather, its beneficial impacts may become into power when anti-PD-1 regimens—that may potentiate immune activities—are administered to TNBC patients.

Original languageEnglish
Pages (from-to)1315-1326
Number of pages12
JournalCancer Immunology, Immunotherapy
Issue number7
StatePublished - 1 Jul 2020


  • Programmed cell death protein 1 (PD-1)
  • Triple-negative breast cancer (TNBC)
  • Tumor necrosis factor receptor 2 (TNFR2)
  • Tumor-infiltrating lymphocytes (TILs)


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