Combining Innate Immunity With Radiation Therapy for Cancer Treatment

The widely shared goal of cancer immunotherapy is to stimulate an immune response of sufficient quality and magnitude to destroy primary malignancies and their metastases. Cancer immunotherapy has taken many cues from the development of successful antimicrobial vaccines.

Antimicrobial vaccines rely on the immune system’s capacity to distinguish self-tissues from infectious non-self so that invading pathogens, and the cells they might infect, could be efficiently identified and eliminated, while sparing healthy tissues. The process of discriminating self from infectious non-self is facilitated by the millions (and in some cases billions) of years of evolutionary divergence that separates vertebrates from the pathogens that infect them.

This separation has given rise to individual proteins and other generalized molecular structures that serve to distinguish microbes from men. In theory, malignant cells that express protein antigens that either are unique to the tumor, vastly over-expressed by the tumor, or whose expression is at least restricted to a narrow range of self-tissues provides a potential immunologic handle whereby tumors may be specifically recognized and destroyed.

In practice, however, it has proven unexpectedly difficult to coax the immune system into vigorously rejecting malignancies, despite repeated demonstrations that tumor-associated antigens can provoke immune responses. In this issue of Clinical Cancer Research, Mason et al. (1) shows, using a murine subcutaneous and lung metastasis sarcomatreatment model, that synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs (characteristic of bacterial DNA) could be given with conventional radiation therapy to greatly augment therapeutic efficacy through an apparent immune-mediated.

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.