Anti-HER2 CD4(+) T-helper Type 1 Response is a Novel Immune Correlate to Pathologic Response Following Neoadjuvant Therapy in HER2-positive Breast Cancer

A progressive loss of circulating anti-human epidermal growth factor receptor-2/neu (HER2) CD4(+) T-helper type 1 (Th1) immune responses is observed in HER2(pos)-invasive breast cancer (IBC) patients relative to healthy controls. Pathologic complete response (pCR) following neoadjuvant trastuzumab and chemotherapy (T + C) is associated with decreased recurrence and improved prognosis. We examined differences in anti-HER2 Th1 responses between pCR and non-pCR patients to identify modifiable immune correlates to pathologic response following neoadjuvant T + C.

Anti-HER2 Th1 responses in 87 HER2(pos)-IBC patients were examined using peripheral blood mononuclear cells pulsed with 6 HER2-derived class II peptides via IFN-γ ELISPOT. Th1 response metrics were anti-HER2 responsivity, repertoire (number of reactive peptides), and cumulative response across 6 peptides (spot-forming cells [SFC]/10(6) cells). Anti-HER2 Th1 responses of non-pCR patients (n = 4) receiving adjuvant HER2-pulsed type 1-polarized dendritic cell (DC1) vaccination were analyzed pre- and post-immunization.
Depressed anti-HER2 Th1 responses observed in treatment-naïve HER2(pos)-IBC patients (n = 22) did not improve globally in T + C-treated HER2(pos)-IBC patients (n = 65). Compared with adjuvant T + C receipt, neoadjuvant T + C – utilized in 61.5 % – was associated with higher anti-HER2 Th1 repertoire (p = 0.048). While pCR (n = 16) and non-pCR (n = 24) patients did not differ substantially in demographic/clinical characteristics, pCR patients demonstrated dramatically higher anti-HER2 Th1 responsivity (94 % vs. 33 %, p = 0.0002), repertoire (3.3 vs. 0.3 peptides, p < 0.0001), and cumulative response (148.2 vs. 22.4 SFC/10(6), p < 0.0001) versus non-pCR patients. After controlling for potential confounders, anti-HER2 Th1 responsivity remained independently associated with pathologic response (odds ratio 8.82, p = 0.016). This IFN-γ(+) immune disparity was mediated by anti-HER2 CD4(+)T-bet(+)IFN-γ(+) (i.e., Th1) – not CD4(+)GATA-3(+)IFN-γ(+) (i.e., Th2) – phenotypes, and not attributable to non-pCR patients’ immune incompetence, host-level T-cell anergy, or increased immunosuppressive populations. In recruited non-pCR patients, anti-HER2 Th1 repertoire (3.7 vs. 0.5, p = 0.014) and cumulative response (192.3 vs. 33.9 SFC/10(6), p = 0.014) improved significantly following HER2-pulsed DC1 vaccination.

Anti-HER2 CD4(+) Th1 response is a novel immune correlate to pathologic response following neoadjuvant T + C. In non-pCR patients, depressed Th1 responses are not immunologically “fixed” and can be restored with HER2-directed Th1 immune interventions. In such high-risk patients, combining HER2-targeted therapies with strategies to boost anti-HER2 Th1 immunity may improve outcomes and mitigate recurrence.

Affiliation

Department of Surgery, University of Pennsylvania Perelman School of Medicine, Rena Rowen Breast Center, 3400 Civic Center Drive, Philadelphia, PA, 19104, USA.

Development of Vaccines for High-Risk Ductal Carcinoma In situ of the Breast

With the widespread use of screening mammography, ductal carcinoma in situ (DCIS) has become the most frequently diagnosed cancerous lesion identified in the breast. Like invasive breast cancer, DCIS is heterogeneous and represents a relatively wide spectrum of diseases.

Low-grade DCIS either rarely develops into invasive disease or progresses slowly to invasiveness over the course of 8 to 10 years. On the other hand, if untreated, high-grade DCIS lesions that display comedonecrosis will likely develop into invasive breast cancers over a 5- to 7-year period. Following current conventional treatment with surgery with wide margins (lumpectomy; ref. 1), lumpectomy plus radiation therapy (2), or mastectomy, the overall prognosis for these patients is excellent. Nonetheless, many patients (at least 30%) require the more aggressive therapeutic option (mastectomy) either because of extensive disease or for fear of cancer recurrence.

The latter remains a significant risk, particularly in younger patients. Fortunately, the relatively long period of latency between the onset of DCIS and development of invasive breast cancer offers an opportunity for novel neoadjuvant interventions. The potential benefits of such neoadjuvant therapies include (a) reduction of risk for subsequent breast cancer, (b) reduction in the psychological effect of the disease related to fear of recurrence, and (c) reduction in the morbidity resulting from surgery and radiation.

The latter would be achieved through diminution in the extent of disease before the application of standard therapies, limiting the need for radiation and decreasing the need for extensive surgical
resections.

Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy

The success of cellular immunotherapies against cancer requires the generation of activated CD4+ and CD8+ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial.

While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases.

While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs.

Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of anti-tumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.

Affiliation

Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA ; Rena Rowen Breast Center, Hospital of the University of Pennsylvania , Philadelphia, PA , USA.

Radiation as Immunomodulator: Implications for Dendritic Cell-Based Immunotherapy

The last decade has witnessed significant progress in the field of cancer immunotherapy. This has, in part, been driven by a growing recognition that elements of the innate immune response can be harnessed to induce robust immunity against tumor-associated targets. Nonetheless, as clinically effective immunotherapy for the majority of cancers remains a distant goal, attention has shifted toward multimodality approaches to cancer therapy, sometimes combining novel immunotherapeutics and conventional therapeutics. The traditional view of radiation therapy as immunosuppressive has been challenged, prompting a re-evaluation of its potential as an adjunct to, or even a component of immunotherapy. Radiation therapy may enhance expression of tumor-associated antigens, induce targeting of tumor stroma, diminish regulatory T-cell activity and activate effectors of innate immunity such as dendritic cells through Toll-like receptor (TLR)-dependent mechanisms. Here, we review recent progress in the field of dendritic cell-based immunotherapy, evidence for radiation-induced anti-tumor immunity and TLR signaling and the results of efforts to rationally integrate radiation into dendritic cell-based immunotherapy strategies.

Affiliation

A  Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania.