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Keywords: Natural killer cell, lectin-like transcript 1, CLEC2D, CD161, breast cancer, prostate cancer,
immunotherapy

INTRODUCTION
Breast cancer is one of the most serious diseases influencing the health of women, whereas prostate cancer
[1]
[2]
threatens the health of men . In the 2019 Cancer Statistics report by Siegel et al. , it was estimated that more
than 170,000 men will be diagnosed with prostate cancer in the United States in 2019. Triple negative breast
cancer (TNBC), a subtype of breast cancer, has the poorest prognosis and highest rate of recurrence and
[3]
metastasis . Cancer recurrence and metastasis is the primary cause of cancer-related deaths and resistance
to previous treatments is commonly seen. The critical functions of the immune system in cancer have been
known for decades, but the transition to immunotherapy as a major method of cancer treatment has only
occurred within the past few years. After the immunoediting hypothesis was suggested, the role of immune
[4]
cells in cancer cell elimination, tolerance, and escape has been recognized . Although our immune system
utilizes both innate and adaptive immune cells to recognize and eliminate abnormal cells, in many situations,
cancer cells are still able to avoid immune surveillance. Cancer cells can adopt several mechanisms to evade
immune surveillance; one mechanism is the upregulation of inhibitory signal pathways of immune cells to
[5]
inhibit the immune response, such as upregulation of PD-L1 in TNBC . Lectin-like transcript 1 (LLT1) is
a natural killer (NK) cell inhibitory ligand that has been described to contribute to the immunosuppressive
[6-9]
properties of glioblastoma, prostate cancer, and triple negative breast cancer . This review highlights breast
and prostate cancer, the function of NK cells, and NK cell-based immunotherapy. Additionally, this review
explores LLT1 as a potential immunotherapeutic target for breast and prostate cancer elimination by NK
cells.

BREAST CANCER AND PROSTATE CANCER
In 2019, there will be approximately 270,000 women diagnosed with breast cancer and 170,000 men diagnosed
[2]
with prostate cancer in the United States . Unlike other cancers, breast cancer and prostate cancer are
primarily gender specific in females and males, respectively. According to the expression level of estrogen
receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), breast cancer
is classified into the subtypes luminal A, luminal B, HER2 positive, and TNBC [10,11] . Compared with the
other subtypes of breast cancer, TNBC has a relatively worse prognosis owning to lack of recognizable
molecular targets and high level of heterogeneity [10,12-14] . Conventional treatments, including chemotherapy
and radiotherapy, are still the primary way to treat TNBC patients. Beneficial results are observed when
patients first begin chemotherapy; however, resistance to the chemotherapy and recurrence have been shown
[15]
after later treatments . BRCA1, BRCA2, ATM, and TP53 are essential genes in the DNA damage response
[16]
signal pathways . Studies suggest mutations in these genes are found in TNBC [16,17] . In TNBC, critical
DNA damage response gene mutations lead to genomic instability, and a higher probability to produce
[18]
neoantigens, which are termed “non-self” to differentiate from “self” . These neoantigens offer promising
targets for immunotherapy.

In the United States, prostate cancer is the second leading cause of cancer-related death in males. Due to
the vital role of the androgen receptor in the development of prostate cancer, androgen deprivation therapy
has become the standard treatment for prostate cancer [19-22] . Prostate cancer recurrence is usually androgen
independent, which is termed castration-resistant prostate cancer [23,24] . Therefore, new treatments are required
for castration-resistant prostate cancer.

NK CELL FUNCTION
NK cells are an indispensable component of immune cells, but their role in immunotherapy has only been
considered in recent years. NK cells were first suggested in tumor immunosurveillance due to studies