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IMMUNITY IN TRIPLE-NEGATIVE BREAST CANCER
Triple-Negative Breast Cancer: Immune Modulation as the New
Treatment Paradigm
Mary L. Disis, MD, and Sasha E. Stanton, MD, PhD
OVERVIEW
Recent studies of tumor lymphocytic immune infiltrates in breast cancer have suggested an improved prognosis associated with
increasing levels of tumor-infiltrating lymphocytes (TIL). Triple-negative breast cancer (TNBC) is the breast cancer subtype that has
the greatest incidence of patients with a robust tumor immune infiltrate, although it is still a minority of patients. Elevated levels of
either intratumoral or stromal T cells are associated with an improved overall survival (OS) and disease-free survival (DFS) in TNBC as
compared with other breast cancer subtypes. TNBC may be immunogenic for several reasons. Subtypes of TNBC have a significant
number of genetic mutations, and the immune system may see the aberrant proteins encoded by these mutations as foreign. Moreover,
TNBC is associated with a prognostic gene signature that also includes B cells. Antibodies secreted by B cells may bind to tumor
antigens and amplify the adaptive immune response that has already been initiated in the tumor. New immune modulatory agents,
including immune checkpoint inhibitors, have shown activity in immunogenic tumors such as melanoma and bladder cancer and have
recently been tested in TNBC. The clinical response rates observed, patterns of response, and adverse event profiles are similar to what
has been described in melanoma where this class of agents has already been approved for clinical use in some cases. Lessons learned
in assessing the immunogenicity of TNBC, potential mechanisms of immune stimulation, and response to immune modulatory drugs lay
the foundation for the development of immune-based therapies in all subtypes of the disease.
The immune system is controlled by a balance of cellular
signals that both initiate immune responses and actively
inhibit inflammation induced by immunity. The ability to
suppress immunity is critical to protect normal tissues from
collateral damage during pathogen-destructive immune responses.
The cells of both the innate (neutrophils, monocytes,
macrophages, and a host of antigen-presenting cells [APC]) and
the adaptive (T and B lymphocytes) immune system are called
on to respond to pathogens or other threats. Working in concert,
innate immune cells are required for T cells and B cells to be
able to identify immunogenic proteins (i.e., antigens in the environment).
Further, innate immune cells produce cytokines
that optimize lymphocytic function. The lymphocytes can then
recognize cells expressing foreign proteins and kill those cells.
The generation of adaptive immunity in the appropriate cytokine
milieu allows for the development of memory cells: longlived
lymphocytes that remain in lymph nodes and readily
respond to the specifıc threat if further exposure occurs.
Proinflammatory type I immunity is the immune response
needed to eliminate cancer. In a type I immune response,
CD4 T-helper (Th) lymphocytes, called Th1, secrete cytokines
such as interferon-gamma (IFN-gamma) and TNFalpha
that activate and enhance the lytic function of CD8
T-lymphocytes. Cytokines produced by type I T cells induce
the upregulation of costimulatory molecules on APC, of the
innate immune system allowing those cells to more effectively
present immunogenic proteins to the T cells. CD8 T
cells are cytolytic, and once they dock on a target through
interaction with antigenic peptide containing major histocompatibility
complex (MHC) molecules on the surface of
that target, they either induce cell senescence or directly lyse
target cells via a series of enzymatic reactions.
Breast cancer is capable of stimulating the immune system.
It is well defıned that some breast tumors have substantial
lymphocytic infıltration, and the more T cells found in the
cancer, the more favorable the prognosis. 1 Most breast cancers,
however, have been infıltrated with few or even no T
cells. 2,3 Breast cancers have modest levels of lymphocytic infıltrates
for many reasons. One is that the immune cells found
in the tumor microenvironment of breast cancer are type II
cells. The CD4 Th2 cells express cytokines such as interleukin
(IL)-10 and IL-6, which dampen destructive immunity. Innate
immune cells and high levels of regulatory T cells (Treg)
in the type II environment secrete substances that both inhibit
the function of CD8 T cells and prevent their migration
to the tumor, producing only a limited number of less active
CD8 T cells available to induce tumor regression. Breast cancer
can secrete substances that influence APC to educate T
From the Tumor Vaccine Group, Center for Translational Medicine in Women’s Health, University of Washington, Seattle, WA.
Disclosures of potential conflicts of interest are found at the end of this article.
Corresponding author: Mary L. Disis, MD, Center for Translational Medicine in Women’s Health, 850 Republican St., Box 358050, University of Washington, Seattle, WA 98109; email: ndisis@uw.edu.
© 2015 by American Society of Clinical Oncology.
asco.org/edbook | 2015 ASCO EDUCATIONAL BOOK
e25