Abstract
The use of specific anti-tumor antibodies has transformed the solid cancer therapeutics landscape with the relative successes of therapies such as anti-HER2 in breast cancer, and anti-EGFR in HNSCC and colorectal cancer. However, these therapies result in toxicity and the emergence of resistant tumors. Here, we showed that removing immune suppression and enhancing stimulatory signals increased the anti-tumor activity of unmodified TA99 antibodies (anti-TYRP1) with a significant reduction of growth of solid tumors and lung metastases in mouse models of melanoma. Immune checkpoint blockade enhanced the efficacy of TA99, which was associated with greater CD8+/Foxp3+, NK1.1+ and dendritic cell infiltrates, suggestive of an increased anti-tumor innate and adaptive immune responses. Further, MEK inhibition in melanoma cell lines increased the expression of melanosomal antigens in vitro, and combining TA99 and MEKi in vivo resulted in enhanced tumor control. Moreover, we found an improved therapeutic effect when YUMM tumor-bearing mice were treated with TA99 combined with MEKi and immune checkpoint blockade (anti-PD1 and anti-CTLA4). Our findings suggest that MEKi induced an increased expression of tumor-associated antigens, which in combination with anti-tumor antibodies, generated a robust adaptive anti-tumor response that was sustained by immune checkpoint inhibition therapy. We postulate that combining anti-tumor antibodies with standard-of-care strategies such as immune checkpoint blockade or targeted therapy, will improve therapeutic outcomes in cancer.
Highlights
It is well accepted that tumor development and progression is usually controlled by immunosurveillance mechanisms in which specific and non-specific immunological responses are constantly mounted against tumor cells [1]
With the use of the B16 and YUMM mouse models of melanoma and the anti-tyrosinase-related protein-1 (TYRP1) mouse monoclonal antibody TA99, we demonstrated that the therapeutic effects of these unmodified anti-tumor antibodies can be enhanced by immune checkpoint blockade (ICB) through the stimulation of both innate and adaptive anti-tumor immune responses
To enhance the therapeutic effects of anti-tumor antibodies by removing immune suppressive regulatory signals, we first tested the combination of anti-tumor antibodies [TA99; anti- tyrosinase-related protein-1 (TYRP1) monoclonal antibodies] with antibody-mediated depletion of T regulatory cells (Treg) cells in the B16 mouse model of melanoma
Summary
It is well accepted that tumor development and progression is usually controlled by immunosurveillance mechanisms in which specific and non-specific immunological responses are constantly mounted against tumor cells [1]. Growing evidence points toward a correlation between high immunogenicity and immune responsiveness of tumors [2]. In melanoma, this concept is supported by findings such as spontaneous remissions, the existence of metastatic tumors without identifiable primary lesions, and the presence of infiltrating T lymphocytes capable of recognizing melanoma-derived antigens in primary tumors and metastatic lesions [3, 4]. Clinical remissions are infrequent and transient in advanced stage solid tumors treated with anti-tumor antibodies, even with concomitant chemotherapy www.oncotarget.com [10, 11]. Clinical successes with anti-tumor antibody therapy (anti-CD20, anti-HER2, anti-EGFR) were exclusively attributed to the interruption of their respective signaling pathways, but recent evidence suggests an essential role for innate as well as adaptive immunity in the therapeutic outcome
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