Innate immunity as a target for novel therapeutics in triple negative breast cancer

ABSTRACT

Introduction

Currently, triple-negative breast cancer (TNBC) has limited therapeutic options beyond chemotherapy and has worse outcomes than other breast cancer subtypes. Initial experience with immune checkpoint blockade for the treatment of TNBC has indicated that modifying the tumor immune response represents a promising direction of investigation. Subsequent studies have led to a deeper understanding of the heterogeneity of this disease and have informed further exploration of numerous potential therapeutic approaches to intervene in the tumor microenvironment (TME).

Areas covered

Initial work in this arena has focused on enhanced definition of checkpoints in activation of an adaptive immune response. In this review, we discuss recent efforts that have looked into components of innate immunity to reverse immunosuppressive phenotypes and augment antitumor immune response.

Expert opinion

Current treatment options for TNBC have been improved with the approval of immune checkpoint inhibitors (ICI) in both advanced and early-stage disease; however, the challenge remains to expand the number of patients that will benefit from immunotherapy. Optimizing the innate immune response represents an opportunity to improve this therapeutic index, and the development of an array of novel agents is underway. Success will depend on precision characterization of the patient TME and selection of ideal combination therapy.

KEYWORDS:

• Breast cancer
• immunotherapy
• innate immunity
• triple-negative breast cancer

Article highlights

• Innate immunity is critical for establishment of an antitumor adaptive immune response, and many of its components are being explored as therapeutic targets in triple-negative breast cancer.

• Immune checkpoint inhibitors benefit only a subset of TNBC patients (including those with elevated PDL1 expression and/or neoantigen production), and this recognition has focused research on not only additional checkpoints but also innate immune function and features of the tumor microenvironment.

• Numerous designs of cancer vaccines are being evaluated alongside costimulatory molecules and cytokines.

• Innate immune agonists and antagonists across a broad range of therapeutic class/strategy aim to reprogram the TME, both minimizing immunosuppressive features and facilitating antigen presentation, cytotoxic immune lymphocyte infiltration, and activation to accomplish tumor cell death.

• Emerging phase 1/2 trials in TNBC patients will capitalize on this array of potential targets by exploring novel combinations likely required to overcome therapeutic resistance to current generation immunotherapy regimens.

This box summarizes key points contained in the article.

Declaration of interest

H Schmidt is an employee and owns stock in GSK. T Borgovan is an employee and owns stock in GSK.

N Yanamandra is an employee and owns stock in GSK. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One referee has received research funding from Roche and Pfizer, participated in advisory boards for Roche, Seagen, AZ and received speaker’s fees from Pfizer, Lilly, Gilead, Seagen, and AZ.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded