Abstract
Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention.
Highlights
Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers and is considered an aggressive subtype due to the greater risk of metastasis within the first few years of diagnosis compared to other subtypes.[1,2,3] With a lack of targetable receptors, TNBC patients remain heavily reliant on combination chemotherapy and there are limited alternatives for those who fail to respond or progress to metastatic disease
Presence of tumor infiltrating memory cells correlates with chemotherapeutic response in TNBC pre-therapy We first evaluated the association of immune infiltrate with chemotherapy
At mid-chemotherapy, the proportions of CD8+ T cells, CD45RO+ cells, and CD8+ CD45RO+ cells were chemotherapeutic response and long-term survival via retro- closely linked to distant relapse (Fig. 2a–c)
Summary
Triple negative breast cancer (TNBC) accounts for 15–20% of all breast cancers and is considered an aggressive subtype due to the greater risk of metastasis within the first few years of diagnosis compared to other subtypes.[1,2,3] With a lack of targetable receptors, TNBC patients remain heavily reliant on combination chemotherapy (commonly incorporating taxanes and anthracyclines4) and there are limited alternatives for those who fail to respond or progress to metastatic disease. 15–35% of patients have a complete pathological response to chemotherapy (cPR) and this is closely associated with a favorable prognosis.[5,6,7,8] predicting response to chemotherapy pre-treatment and those patients at most risk of relapse after a partial or lack of response to chemotherapy is difficult and is an essential area of research for individualized treatment strategies in this subtype. This is important in adjuvant setting where cPR cannot be measured. CD8+ T lymphocytes are key players in antitumor immunity and their intratumoral accumulation has been linked to favorable outcomes in a number of cancers, including breast, where their high proportions correlate with enhanced survival and response to chemotherapy.[12,13] Further interrogation of these populations has revealed that antigen experienced T cells (CD45RO+ CD8+) predict favorable outcomes in non-small cell lung cancer and colorectal cancer.[14,15,16] New advances in singlecell immune profiling have supported a link between particular CD8+ T cell subsets and reduced risk of disease progression, whereby an enhanced tissue resident memory Tcell signature (TRM) was associated with improved patient survival
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