The attention has been increasingly garnered to “cancer immunotherapy” because of its efficacy in several cancer types (1–5). However, the target for cancer immunotherapy is largely individualized or personalized at present and most of the targets are only distributed in a few of cancer types rather than all cancer types (1). Moreover, these molecular targets are not cancer-specific rather required for normal cell functions. Therefore, the bottleneck for current immunotherapy is lack of a specific but broad spectral target or antigen which is widely expressed on both hematopoietic and solid cancers. Recently, we have found that the PIWIL2-like (PL2L) protein 60, a product of alienation-activated PIWIL2 gene by intragenic promoter (6, 7), is widely expressed in various hematopoietic and solid tumors, mediating tumorigenesis through promoting tumor cell proliferation and inhibiting apoptosis as well (8).
The PIWIL2 is usually expressed in testis (9–11), but can be activated in somatic cells upon DNA damages to promote DNA repair through remodeling chromatin (12). It plays crucial roles in self-renewal and maintenance of germline stem cells (13, 14). Recent studies have indicated that the ectopic expression of PIWIL2 has been observed in various types of primary tumors and tumor cell lines (8, 15), including breast cancer (16), cervical cancer (17), gastric cancer (18), acute myeloid leukemia (19), colorectal cancer (20), colon cancer (21), ovarian cancer (22) and testicular germ cell tumors (23).
It has been reported that PIWIL2 can promote tumorigenesis through regulating several signal transduction pathways (8, 24–31) and inhibiting apoptotic death of tumor cells via activation of Stat3/Bcl-XL pathway (15, 24). However, the function of PIWIL2 in tumor development remains controversial, because most of the commercial available antibodies specific for PIWIL2 could not distinguish the full length PIWIL2 from its variants (8). In the primary breast and cervical cancers, full length PIWIL2 proteins were detected mainly in apoptotic tumor cells but little in living tumor cells (8). In contrast, PIWIL2 variants PL2L proteins, such as PL2L60, are abundantly detected in various types of tumor tissues and tumor cell lines (8, 23), suggesting that the tumorigenic function of PIWIL2 might be mediated mainly by PIWIL2 variants (31).
We and others have found that PIWIL2 has multiple variants including PL2L80, PL2L80A, PL2L60, PL2L60A, PL2L50 and PL2L40 (8, 23, 31). Some of the variants appear to be transcribed by intragenic promoters rather than a canonical promoter (6, 7). While full length PIWIL2 can mediate DNA repair acting as a barrier gene to the initiation of tumorigenesis and promote apoptotic cell death in tumor tissues (8, 32), its variants such as PL2L60 (6, 8) and PL2L60A (23) can promote tumorigenesis. Among the variants mentioned above, PL2L60 is predominantly expressed in precancerous stem cells (pCSCs) as well as in various types of human and murine tumor cell lines with a level much higher than full length PIWIL2 (8, 33–35). PL2L60 can promote tumor cell survival and proliferation in vitro through up-regulation of STAT3 and BCL2 genes. It can also coordinate with NF-κB to promote tumorigenesis, probably representing a common pathway for the development of tumors in various types of tissues (8, 36, 37). Importantly, peptides derived from PL2L60 can serve as strong immunogens targeting various types of cancers (8, 38). In addition, PL2L60 is also detected in the testicular cells of mice, suggesting its roles in gametogenesis or development (6, 23).
In this study, we investigated the efficacy of mAb KAO3 to PL2L60 in immunotherapy of cancers, which was generated in our laboratory (8). It demonstrated a unique capability to directly induce apoptosis of cancer cells and to inhibit cell proliferation through arresting cell cycle. It effectively inhibited tumorigenesis of pCSCs in the severe-combined immunodeficient (SCID) mice and furthermore suppressed established tumor growth when injected intratumorally into lymphoma, breast cancer, lung cancer and cervical cancer. Collectively, the anti-PL2L60 mAb KAO3 is a potentially useful drug for immunotherapy of various types of cancers.