Molecular Pathways: Involvement of Immune Pathways in the Therapeutic Response and Outcome in Breast Cancer

Abstract

The immune system could mediate the antitumor activity of several anticancer treatments. Several chemotherapy compounds, including anthracyclines and oxaliplatin, induce immunogenic cell death that in turn activates antitumor immune response. Trastuzumab induces antibody-dependant cell-mediated cytotoxicity. On the basis of this background, immune markers have recently been the focus of intense translational research to predict and monitor the efficacy of treatments. Gene expression arrays and immunohistochemistry have assessed immune activation and infiltration by macrophages, natural killer, and T and B lymphocytes. Using these approaches, several retrospective analyses of large trials have shown that activation of immune pathway may predict treatment efficacy and outcome in patients with breast cancers. As examples, intratumoral infiltration by lymphocytes and interferon-response in primary tumor predicted the efficacy of neoadjuvant chemotherapy. Intratumoral infiltration by lymphocytes was associated with good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy. More recently, it has been suggested that lymphocyte infiltration could also predict efficacy of trastuzumab. Finally, small retrospective studies have suggested that postchemotherapy lymphocyte infiltrates could be associated with better outcome in patients who did not reach pathologic complete response. This body of evidence suggests that assessing immune infiltration and activation could be useful in the future to stratify breast cancer patients. In addition, they provide evidence for the development of immunotherapies in breast cancer patients.

TLR4 is essential for dendritic cell activation and anti-tumor T-cell response enhancement by DAMPs released from chemically stressed cancer cells

“…Finally, at 18 h, the release of HMGB1 from dying tumor cells can be observed. 30,31 In contrast to the results for doxorubicin, our data showed that the levels of HSP70 and HMGB1 peaked at 30 h after exposure to OXA and 5-Fu and gradually decreased afterward. Thus, we evaluated the anti-tumor effect of adjuvant immunotherapy induced by a DC vaccine, including protocols for maturing DCs pulsed with 30-h supernatants.…”

Trastuzumab as a preoperative monotherapy does not inhibit HER2 downstream signaling in HER2-positive breast cancer

“…Trastuzumab, a mAb, dramatically improves the response rate and progression-free and overall survival of patients with metastatic disease (15). However, the exact mode of action of trastuzumab remains partly elucidated, and several studies have suggested that the inhibition of oncogenic signaling may not be the main mode of action (21,22), in particular when trastuzumab is administered alone for chemotherapy-naïve patients (25,28).…”

“…Several studies have proposed that the behavior and mechanism of action of trastuzumab may be drastically altered in vitro and in vivo (19,21), and that the relative involvement of signaling inhibition vs. ADCC could be an important determinant of the activity of trastuzumab (25).…”

Mapping spatial heterogeneity in the tumor microenvironment: a new era for digital pathology

“…In the right context, different subclasses of lymphocytes may exhibit entirely different phenotypes with pro-or anti-tumor roles. 30,34,39 It is thus of paramount importance to discriminate them. One of the first studies to apply rigorous spatial statistics on data from fully automated image analysis investigated clustering patterns of B cells and T cells in healthy and tumor-draining lymph nodes in breast cancer patients.…”