Breast Cancer Immunology and Immunotherapy: Targeting the Programmed Cell Death Protein-1/Programmed Cell Death Protein Ligand-1

Breast Cancer Immunology and Immunotherapy: Targeting the Programmed Cell Death Protein-1/Programmed Cell Death Protein Ligand-1

Breast cancer has historically been regarded as an immunogenically “cold” tumor, meaning it typically does not elicit a strong immune response. However, the advent of immune checkpoint inhibitors has revolutionized the treatment landscape, making immunotherapy an emerging modality for breast cancer. This review delves into the immune system’s role in breast cancer, the immune features of the disease, and the use of programmed cell death protein-1 (PD-1) and programmed cell death protein ligand-1 (PD-L1) inhibitors in its treatment. The focus is on understanding how immunotherapy can be optimized for breast cancer, particularly in subtypes such as triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which exhibit high T lymphocyte infiltration and mutation burden.

Introduction

Breast cancer is the most common cancer among women globally, with 2.1 million cases diagnosed in 2018. In China, it ranks as the sixth leading cause of cancer-related deaths, with approximately 268,600 new cases reported in 2015. Despite advances in screening, detection, and treatment, metastatic breast cancer remains largely incurable due to its heterogeneous nature and resistance to therapy. Immunotherapy, particularly immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and PD-1, has shown promise in enhancing survival in advanced cancers such as melanoma, renal cancer, and lung cancer. Although breast cancer has traditionally been considered poorly immunogenic, recent clinical trials involving checkpoint inhibitors, either as monotherapy or in combination with other strategies, have yielded encouraging results. This review explores the immune system’s role in breast cancer, the disease’s immune features, and current immunotherapy strategies, with a focus on PD-1/PD-L1 inhibitors.

Overview of the Immune System and Breast Cancer

The immune system plays a dual role in cancer, both suppressing tumor growth and promoting tumor progression. The concept of immune surveillance, first proposed by Ehrlich in 1909 and refined by Burnet in 1970, suggests that the immune system identifies and eliminates malignant cells. Schreiber’s theory of “immunoediting” further illustrates that the immune system not only protects against tumor formation but also shapes tumor fate through three phases: elimination, equilibrium, and escape. During the escape phase, tumors develop mechanisms to evade immune surveillance, such as the loss of major histocompatibility complex (MHC) expression, the presence of immune inhibitory receptors (e.g., PD-1, CTLA-4, and lymphocyte activation gene [LAG]-3), and the creation of an immunosuppressive microenvironment through cytokines and regulatory immune cells.

In breast cancer, different subtypes evade the immune system through distinct mechanisms. Hormone receptor (HR)-positive breast cancer often lacks tumor antigens and exhibits low MHC-I expression, making it less recognizable to the immune system. Estrogen also plays an immunosuppressive role by polarizing the immune response toward a T helper 2 (Th2) rather than a T helper 1 (Th1) response. HER2-positive breast cancer shows an inverse correlation between MHC-I expression and HER2 overexpression, leading to immune evasion. TNBC, the most immunogenic subtype, escapes immune surveillance by developing an immunosuppressive tumor microenvironment.

Immunogenicity of Breast Cancer

The identification of tumor antigens by the immune system is crucial for triggering anti-tumor immunity. Neo-antigens, which arise from gene mutations, viral oncogenes, or overexpressed proteins, play a significant role in immunotherapy. The tumor mutation burden (TMB), or the average number of somatic mutations per cancer cell, is associated with antigenicity. Advances in sequencing technology have revealed that breast cancer has a lower median TMB compared to more immunogenic “hot tumors” like lung cancer and melanoma. However, TMB varies significantly across breast cancer subtypes. HER2-positive breast cancer exhibits a higher TMB and increased immune gene expression compared to HER2-negative subtypes. Estrogen receptor (ER)-negative tumors have a higher somatic mutation load (SML) than ER-positive tumors, with high SML in ER-positive tumors associated with poor overall survival (OS). Metastatic tumors generally show a higher TMB than primary tumors, reflecting accumulated genomic alterations during tumor evolution.

Specific mutations, such as those in BRCA1 and BRCA2, are associated with high mutational loads due to defects in homologous repair (HR) pathways. Mismatch repair (MMR) deficiency, another DNA repair mechanism, is also linked to increased immunogenicity. Tumors with MMR deficiency respond well to immune checkpoint inhibitors, leading to the approval of the anti-PD-1 monoclonal antibody pembrolizumab for advanced or recurrent solid tumors. However, MMR deficiency is rare in breast cancer, occurring in less than 1% of cases.

Role of Tumor-Infiltrating Lymphocytes in Breast Cancer

Tumor-infiltrating lymphocytes (TILs) are linked to pre-existing anti-tumor immunity and clinical responses in breast cancer. High levels of TILs are associated with better prognosis in TNBC and HER2-positive breast cancer, making them potential biomarkers for identifying patients who may respond well to immunotherapy. However, the prognostic value of TILs remains somewhat conflicting across studies. In neoadjuvant treatment, TILs are considered reliable biomarkers for predicting pathological complete response (pCR), particularly in TNBC and HER2-positive subtypes.

Different subsets of TILs provide varying prognostic information. Increased CD8+ T cells are associated with favorable outcomes, while the role of CD4+ T cells is more complex due to their diverse functional characteristics. Regulatory T cells (Tregs) play a significant role in creating an immunosuppressive tumor microenvironment, and their presence is associated with poor prognosis in ER+ breast cancer but not in HER2+/ER- subtypes.

PD-1/PD-L1 Pathway in Breast Cancer

The PD-1/PD-L1 pathway is a major immune checkpoint that inhibits immune responses. PD-1 is expressed on T cells, B cells, natural killer T cells, monocytes, and dendritic cells, while PD-L1 is expressed on antigen-presenting cells and tumor cells. The binding of PD-L1 to PD-1 attenuates lymphocyte activation, allowing tumors to evade immune surveillance.

In breast cancer, PD-L1 expression ranges from 20% to 34% and is heterogeneous across subtypes. It is more commonly expressed in aggressive subtypes such as TNBC and HER2-enriched breast cancer. The prognostic value of PD-L1 expression is debated, with some studies associating it with poor outcomes and others linking it to better survival, particularly in TNBC. PD-L1 expression is also associated with the activation of immune-related pathways, such as interferon (IFN)-α, IFN-γ, and tumor necrosis factor (TNF)-α, providing a rationale for targeting this pathway in immunotherapy.

Anti-PD-1/PD-L1 Agents in Breast Cancer

The use of anti-PD-1/PD-L1 agents in breast cancer has been explored in various clinical trials, with mixed results. Monotherapy with these agents has shown limited efficacy, particularly in TNBC and HER2-positive breast cancer. For example, the KEYNOTE-012 trial, which evaluated pembrolizumab in TNBC, reported an overall response rate (ORR) of 18.5% in PD-L1-positive patients. Similarly, the KEYNOTE-086 trial showed an ORR of 21.4% in untreated TNBC patients with PD-L1 expression ≥1%. However, phase III trials like KEYNOTE-119 have yet to confirm these findings.

Anti-PD-L1 inhibitors, such as atezolizumab and avelumab, have also been investigated. The PCD4989g trial reported an ORR of 10% for atezolizumab monotherapy, with higher responses in first-line treatment subsets. The JAVELIN trial showed an ORR of 8.3% in TNBC patients treated with avelumab. Despite these modest results, PD-L1 expression and TIL infiltration appear to be associated with better responses, although their use as biomarkers remains controversial.

Combination Therapies with Anti-PD-1/PD-L1 Agents

Given the limited efficacy of monotherapy, combination strategies have been explored to enhance the therapeutic potential of anti-PD-1/PD-L1 agents. These strategies include combining checkpoint inhibitors with chemotherapy, molecularly targeted therapies, radiotherapy, and other immunotherapies.

Combination with Chemotherapy

Chemotherapy has traditionally been considered immunosuppressive, but recent studies suggest it can augment anti-tumor immunity when combined with anti-PD-1/PD-L1 agents. Mechanisms include the induction of immunogenic cell death (ICD), which releases tumor antigens and promotes dendritic cell maturation, and the reduction of immunosuppressive cells like Tregs and myeloid-derived suppressor cells (MDSCs). Clinical trials have evaluated combinations of pembrolizumab with cytotoxic agents such as capecitabine, paclitaxel, and eribulin, with varying results. The TONIC trial, which evaluated different induction treatments before nivolumab administration, found that doxorubicin followed by nivolumab was the most effective strategy, with an ORR of 35%.

The IMpassion130 trial, which combined atezolizumab with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), showed significant improvements in progression-free survival (PFS) and overall survival (OS) in PD-L1-positive TNBC patients. Based on these results, atezolizumab was approved for the treatment of unresectable locally advanced or metastatic TNBC with PD-L1 expression.

Combination with Molecularly Targeted Therapies

Combining anti-PD-1/PD-L1 agents with HER2-targeting therapies has shown promise in HER2-positive breast cancer. Trastuzumab, a HER2-targeting monoclonal antibody, has immunomodulatory effects that synergize with checkpoint inhibitors. The PANACEA trial evaluated trastuzumab combined with pembrolizumab in HER2-positive breast cancer, showing a response rate of 15% in PD-L1-positive patients. Other combinations, such as T-DM1 (ado-trastuzumab emtansine) with atezolizumab, have also been explored, with benefits observed in PD-L1-positive tumors.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, such as palbociclib and abemaciclib, have been combined with anti-PD-1/PD-L1 agents to enhance anti-tumor immunity. Preclinical studies suggest that CDK4/6 inhibitors increase tumor immunogenicity and suppress Treg proliferation, leading to synergistic effects with checkpoint blockade. Clinical trials are ongoing to evaluate these combinations in hormone receptor-positive breast cancer.

Poly (ADP-ribose) polymerase (PARP) inhibitors, which target DNA repair pathways, have also been combined with anti-PD-1/PD-L1 agents. Tumors with BRCA1/2 mutations, which are associated with high mutational loads, may benefit from this combination. The MEDIOLA trial, which combined olaparib with durvalumab, reported a disease control rate (DCR) of 80% at 12 weeks in BRCA-mutated HER2-negative breast cancer.

Combination with Radiotherapy

Radiotherapy can enhance the efficacy of anti-PD-1/PD-L1 agents by inducing ICD and promoting systemic immune responses. The abscopal effect, where radiation induces tumor shrinkage at distant sites, has been observed in preclinical models. Clinical trials are investigating the combination of pembrolizumab with radiotherapy in metastatic TNBC, with promising early results.

Combination with Other Immunotherapies

Combining anti-PD-1/PD-L1 agents with other immunotherapies, such as CTLA-4 inhibitors, has shown synergistic effects in other cancers. Clinical trials are exploring this combination in breast cancer, with modest responses observed. Other strategies include combining checkpoint inhibitors with cancer vaccines, oncolytic viruses, and immunosuppressive agents like IDO inhibitors and adenosine A2a receptor antagonists.

Conclusions and Perspectives

Breast cancer, traditionally viewed as an immunogenically “cold” tumor, has shown potential for immunotherapy, particularly in subtypes like TNBC and HER2-positive breast cancer. While single-agent anti-PD-1/PD-L1 inhibitors have shown limited efficacy, combination strategies with chemotherapy, molecularly targeted therapies, radiotherapy, and other immunotherapies offer promising avenues for enhancing therapeutic outcomes. The development of predictive biomarkers, such as PD-L1 expression, TIL infiltration, and TMB, is crucial for identifying patients who may benefit most from these treatments. Ongoing clinical trials continue to explore the potential of immunotherapy in breast cancer, offering hope for improved outcomes in this challenging disease.

doi.org/10.1097/CM9.0000000000000710

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