Natural and therapy-induced immunosurveillance in breast cancer

Abstract

The immunosurveillance theory postulates that tumors evolve and progress in an uncontrolled fashion only when anticancer immune responses fail. Natural immunosurveillance clearly influences human breast cancer (BC) progression because the prognosis of BC patients is dictated by the density, composition and activity of the tumor immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapeutic regimens commonly employed for the treatment of BC affect the tumor immune infiltrate, and accumulating data suggest that the clinical efficacy of these treatments is largely determined by T cell-dependent tumor-specific immune responses. In addition, the mechanism of action of targeted anticancer therapeutics, such as the erb-b2 receptor tyrosine kinase 2 (ERBB2)-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system. In this Review, we discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of BC. Moreover, we point out that the successful implementation of immunotherapy to BC management requires the optimization of current immunotherapeutic regimens and the identification of immunological biomarkers that enable improved risk stratification and the design of personalized, dynamic treatment plans.

HER2 signaling regulates the tumor immune microenvironment and trastuzumab efficacy

“…Accordingly, tumors dependent on HER2 signaling and classified by our TRAR model as responsive to trastuzumab treatment (TRAR-low) were found to express higher levels of CCL2 and to be more infiltrated by CD68+ cells than non-HER2 addicted, trastuzumab resistant (TRAR-high) tumors. This supports the reported concept that trastuzumab, through its constant fragment Fc, mediates anti-tumor cytotoxic effects by rendering tumor cells recognizable by macrophages 7,19 other than NK cells. Results obtained in an animal model using an anti-CCL2 monoclonal antibody, which indicated improved monocyte/macrophage (CD11b+ F4/80+) infiltration in the TME associated with higher trastuzumab anti-tumor inhibitory activity, supported the role of these immune cells in trastuzumab efficacy.…”

“…As dendritic cells express the Fcγ receptor, they may also contribute to the responsiveness of TRAR-low tumors to trastuzumab by taking up tumor cell fragments opsonized by the antibody and priming CD4+ or CD8+ T lymphocytes. 7 …”

“…3 Recently, analyses of gene expression profiles of tumor blocks from patients enrolled in clinical trials support a relationship between tumor dependence on HER2 signaling (HER2-E by PAM50) and trastuzumab sensitivity. 4,5 Moreover, based on increasing evidence of the role of both innate and adaptive immunity in trastuzumab mechanism of action, 6,7 immune-related information such as tumor infiltrating lymphocyte count or immune-related signatures were explored and found to be predictive of trastuzumab benefit in several studies. 8 In this context, through transcriptome profiling of archival formalin-fixed paraffin embedded (FFPE) tumor blocks from HER2+ cases treated with adjuvant trastuzumab in our Institute during routine clinical practice, 9 we identified BCs exquisitely sensitive to treatment as those with both tumor dependence on HER2 signaling by PAM50 classification, as well as enriched in immune genes, 9 supporting the predictive power of both addiction to HER2 signaling and immune infiltration because of their ability to identify the same tumors.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…87-103 However, TAAs often display limited antigenicity (reflecting the fact that they generally resemble self-antigens that are covered by tolerance). 104-106 Moreover, tumors emerge and evolve as they become able to escape natural immunosurveillance, 107-110 either because the lose expression of potentially antigenic proteins, and/or because they establish an immunosuppressive milieu that enforces local tolerance. 111-116 Thus, besides a few exceptions and despite promising preclinical findings, 117 multiple studies demonstrate that peptide-based vaccines employed as standalone adjuvanted interventions have limited clinical activity (although they generally cause some signs of tumor-targeting immunity).…”

Positive impact of autophagy in human breast cancer cells on local immunosurveillance

“…9 Driven by the aforementioned results obtained in mouse models, we decided to evaluate the possible impact of autophagy in breast cancer cells on the tumor microenvironment. For this, we quantified the intratumoral and peritumoral density of CD8 C cytotoxic T lymphocytes (CTL), FOXP3 C Tregs and yet another immunosuppressive cell type, namely CD68 C tumor-associated macrophages (TAMs).…”