Immunosurveillance in Breast Cancer

Successful implementation of immunotherapy in breast cancer management requires the optimisation of current immunotherapeutic regimens and the identification of immunological biomarkers

In an article published in Nature Medicine, G. Kroemer et al. discuss accumulating preclinical and clinical evidence suggesting that immunosurveillance is critical for disease outcome in breast cancer patients, and propose that introducing immunomodulators as part of early therapeutic regimens against breast cancer could markedly improve the clinical management.

For decades, cancer was considered a purely cell-autonomous disease. Anticancer therapies were therefore designed to target the specific vulnerabilities of malignant cells. Recently, this cancer cell–centric view expanded to accommodate the concept of immunosurveillance, which postulates that nascent tumours are generally eliminated by the immune system, unless malignant cells manage to escape immune recognition or generate an immunosuppressive environment.

Natural immunosurveillance clearly influences human breast cancer progression because the prognosis of breast cancer patients is dictated by the density, composition and activity of the tumour immune infiltrate at diagnosis. Moreover, chemotherapeutic and radiotherapy regimens used for the treatment of breast cancer affect the tumour immune infiltrate. In addition, the mechanism of action of targeted anticancer therapeutics, such as the HER2-targeting agent trastuzumab, involves the innate and adaptive arms of the immune system.

In their review article, the authors discuss these findings as well as preliminary evidence indicating that immunotherapy constitutes a promising option for the treatment of breast cancer. In particular, they discuss the topics such as expression of immunity-related genes at diagnosis, the immune infiltrate at diagnosis, external factors modulating the immune infiltrate, immunogenic cell death, HER2 as an ‘unintentional’ immunotherapy target, and experimental immunotherapies.

Several immunotherapies approved by regulatory agencies worldwide for the treatment of various tumours, including melanoma and non-small cell lung carcinoma (NSCLC), demonstrate that the immunosurveillance model is clinically relevant. Moreover, accumulating evidence suggests that the long-term efficacy of some, if not all, conventional chemotherapeutics, targeted anticancer agents and radiotherapies, hinges on their capacity to reinstate immunosurveillance.

Unlike melanoma and NSCLC, breast cancer has not been intensively investigated for its susceptibility to immunotherapy in clinical settings. Perhaps this reflects the relatively low mutational load of breast cancer cells, which may be interpreted to indicate that breast cancer patients might not be especially sensitive to immunotherapy.

Accumulating preclinical and clinical evidence suggest that immunosurveillance is critical for disease outcome in breast cancer patients

Immunotherapeutic regimens against breast cancer

Immunotherapeutic regimens against breast cancer that have been investigated in preclinical settings and/or are currently being evaluated in clinical trials.

Chemotherapeutic and radiotherapy regimens currently employed in breast cancer patients are particularly efficient if they elicit a robust tumour-targeting immune response. This scenario applies also to trastuzumab, which not only neutralizes the trophic function of HER2, but also elicits an initial NK-mediated antibody-dependent cellular cytotoxicityresponse that is presumably followed by the priming of CD8-positive T lymphocyte-dependent immunity.

Preliminary evidence indicates that blocking immunological checkpoints with anti–PD-1 monoclonal antibodies can mediate therapeutic effects in triple-negative breast cancer patients, further supporting the clinical relevance of breast cancer immunosurveillance. Results obtained in mouse breast cancer models indicate that PD-1–targeting monoclonal antibodies could be advantageously combined with peptide-based vaccines, as well as with some other pharmacological agents. Alternative checkpoint blockers (or alternative immunostimulatory agents) may be more active than CTLA4- or PD-1–targeting monoclonal antibodies in specific breast cancer subtypes. However, future studies should investigate the possibilities in detail.

High levels of tumour infiltrating lymphocytes (TILs) at time of diagnosis have been shown to correlate with improved disease outcome in patients with non-metastatic, basal-like breast cancer treated with standard therapeutic regimens, as well as in those with primary HER2-enriched breast cancer who are receiving trastuzumab. Importantly, tumour infiltration at time of diagnosis and/or other signs of an ongoing immune response against malignant cells could also indicate whether or not patients are likely to respond to various forms of immunotherapy, and hence could guide medical decisions on patient enrollment in clinical studies of this type.

Breast cancer lesions that are devoid of TILs still present a major clinical challenge. The authors wrote that a number of approaches might be used to improve anticancer immune responses in this context. First, the local instillation of T cell–recruiting factors might be useful for the treatment of tumours that are defective in type I IFN signaling pathways. Second, defects in MHC class I expression might be reverted or functionally bypassed. Third, exome sequencing may be used to detect mutations yielding potentially immunogenic breast cancer-associated antigens, which would open up the possibility of creating highly personalised peptide-based vaccines.

The authors suspect that the discovery of optimal immunological biomarkers in breast cancer patients is just at its beginning. Methods allowing for the accurate detection of breast cancer-associated antigens, cancer cell–intrinsic mechanisms of immunosubversion and the functional investigation of the immune infiltrate remain to be developed.

The authors declared no financial interests.

Kroemer G, Senovilla L, Galluzzi L, et al.Natural and therapy-induced immunosurveillance in breast cancer. Nature Medicine 2015; 21: 1128–1138. doi:10.1038/nm.3944