The multifaceted role of STAT3 in enhancing tumor growth by tumor cell intrinsic as well as extrinsic (stromal and immune modulatory) mechanisms is well documented. Elevated STAT3 in tumor cells can lead to increased expression of cytokines, such as IL-6, which can create an immune suppressive environment in the tumor stroma. In addition, STAT3 signaling in cells of the immune system has the potential to contribute to an immune suppressive environment by several mechanisms, including suppression of dendritic cell (DC) maturation and function, enhanced myeloid derived suppressor cell (MDSC) activity, and suppression of T-cell mediated antitumor activity. An immune suppressive environment can reduce the antitumor activity of checkpoint inhibitors such as anti-PD-L1 antibodies by suppressing the ability of T-cell mediated immunity to respond to checkpoint reversal. Therefore, we hypothesized that inhibition of STAT3 has the potential to increase the anti-tumor effects of immune checkpoint inhibitors.
To investigate this hypothesis, we explored the ability of a mouse STAT3 targeted antisense oligonucleotide (ASO) to enhance the antitumor activity of an anti-PD-L1 mAb in a syngeneic murine tumor model. In mice bearing subcutaneous CT-26 tumors, the combination of the STAT3 ASO plus an anti-PD-L1 mAb provided greater antitumor activity than either agent alone. Increased activity was observed when treatment was initiated soon (2 days) after tumor implantation, as well as when treatment was initiated after tumors were established (~150 mm3). When treatment was initiated soon after tumor implantation, single agents as well as the combination were initially effective, but the combination led to long term suppression of tumor growth in a greater percentage of mice (80% for the combination, vs. 20% for single agents). When treatment was initiated after tumors were established, STAT3 ASO or anti-PD-L1 antibody as single agents had significant initial antitumor activity (55% after 14 days of treatment). However, the single agent activity was transient, with the tumor growth rate returning to that of vehicle control (5 day doubling time) after two weeks of treatment. In contrast, the combination treatment led to a sustained reduction in mean tumor growth rate (15 days doubling time), and regression in 20 - 30% of tumors after four weeks of treatment. Treatment with the STAT3 ASO was associated with tumor infiltrating leukocyte changes consistent with enhanced antitumor immunity, including an increase in CD8+ effector T-cells. Combination benefit for STAT3 ASO plus anti-PD-L1 antibody was also observed in other immunocompetent murine tumor models.
The data indicate that, in these models, inhibition of STAT3 has immunomodulatory activity, and can enhance the activity of immune checkpoint inhibitors, such as those targeting PD-L1.
Citation Format: Rich Woessner, Patricia McCoon, Kirsten Bell, Rachel DuPont, Mike Collins, Deborah Lawson, Prasad Nadella, Lourdes Pablo, Corinne Reimer, Vasu Sah, Paul Lyne. STAT3 inhibition enhances the activity of immune checkpoint inhibitors in murine syngeneic tumor models by creating a more immunogenic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A93.
- ©2015 American Association for Cancer Research.