If we build it they will come: targeting the immune response to breast cancer

Abstract

Historically, breast cancer tumors have been considered immunologically quiescent, with the majority of tumors demonstrating low lymphocyte infiltration, low mutational burden, and modest objective response rates to anti-PD-1/PD-L1 monotherapy. Tumor and immunologic profiling has shed light on potential mechanisms of immune evasion in breast cancer, as well as unique aspects of the tumor microenvironment (TME). These include elements associated with antigen processing and presentation as well as immunosuppressive elements, which may be targeted therapeutically. Examples of such therapeutic strategies include efforts to (1) expand effector T-cells, natural killer (NK) cells and immunostimulatory dendritic cells (DCs), (2) improve antigen presentation, and (3) decrease inhibitory cytokines, tumor-associated M2 macrophages, regulatory T- and B-cells and myeloid derived suppressor cells (MDSCs). The goal of these approaches is to alter the TME, thereby making breast tumors more responsive to immunotherapy. In this review, we summarize key developments in our understanding of antitumor immunity in breast cancer, as well as emerging therapeutic modalities that may leverage that understanding to overcome immunologic resistance.

Keywords: Breast cancer; Tumour immunology.

Fig. 1

TCGA breast cancer subtype and percentage of corresponding immune subtype. (Generated from raw data in supplemental Fig. S1D in Thorsson et al.)

Fig. 2

Interaction between the innate and adaptive immune system is vital for immune recognition and elimination of breast tumors. Activation of antigen presenting cells, natural killer cells, macrophages and engagement of T-cells and B-cells through the release of host-derived cytokines plays a central role to tumor destruction. To evade the immune system, tumors release cytokines and skew the tumor microenvironment to a more immunosuppressive environment through inhibiting CD8⁺ T cells, NK cells, dendritic cell maturation and through increasing Tregs and tumor associated macrophages (TAMs). Tumors also reduce antigen presentation of tumor-associated antigens (TAAs) on the tumor surface, and major histocompatibility complex (MHC) expression and alter the antigen presentation machinery (effector cells) to further reduce immune recognition. As this complex web of interactions demonstrates, there are multiple opportunities for the use of immunotherapeutic drug combinations in breast cancer. Figure Key: Blue boxes = targets for immunotherapy drugs; Black boxes = cytokines released by immune cells or tumor; green arrows = activation; red dotted line = inhibiton

Fig. 3

Innate immune cell infiltrates in breast cancer microenvironment. Triple negative breast tumors (CK) with natural killer cells (NK; CD16, CD56), myeloid cells (CD16, CD11b), and macrophage (CD68) infiltration in addition to expression of the immune inhibitory enzyme indoleamine 2,3-dioxygenase (IDO). a Breast tumor (CK) with a predominance of NK cells along with focal IDO expression by macrophages and myeloid cells. b Breast tumor (CK) with a myeloid cell predominance (CD16, CD11b). c Breast tumor (CK) with NK cells (CD16, CD56), myeloid (CD16, CD11b), macrophage (CD68) and tumor (CK) in addition to IDO expression. d Breast tumor (CK) with expression of major histocompatibility 1 (MHC-1). The areas of tumor expressing both CK (red) and MHC-1 (yellow) markers result in an orange hue while areas of tumor that have lost MHC-1 expression are of red color only. e Breast tumor (CK) with expression of CD3⁺ T-cells expressing lymphocyte-activation gene 3 (LAG3) in contact with tumor cell nest. All images were created by Houssein Abdul Sater using MIBITracker open resource software (https://mibi-share.ionpath.com) by IONPath. FFPE breast cancer tissue was stained and imaged using multiplexed ion beam imaging by time-of-flight (MIBI-TOF)