Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth—Response
Authors: Byungsuk Kwon
Journal: Cancer Research (2018)

Although pioneering in vitro studies by Schwarz and colleagues suggest that CD137 ligand (CD137L) signaling plays an important role in various aspects of immunity (1), their observations have been barely proven in animal models. In in vivo conditions, it is technically difficult to separate functional events occurring as a result of CD137-CD137L bidirectional signaling. Similar to CD137, CD137L is suggested to be a costimulatory molecule (2), thus strengthening a primary signal such as pattern recognition receptors and cytokines. Cells interacting with CD137L would define the property of CD137L signaling and the fate of CD137L-expressing cells. For example, NK cells recruited during ischemia reperfusion elicit renal inflammation through engaging CD137L in tubular epithelial cells, a key amplification point for tissue inflammation (3). There is a general consensus that CD137L signaling promotes inflammation during its early phases. However, little is known about functions of CD137L signaling at late phases of inflammation when inflammation subsides and tissue repair mechanisms are mobilized.It has been a mystery for a long time why CD137−/− mice have a hyperresponse to antigen challenge or after induction of injury (4). Now, it is becoming clear that this phenomenon is due to lack in CD137L signaling in many cases (5, 6). Unpublished data of our group and another group (personal communications with YJ Kang, Scripps Research Institute) and a report (7) show that tissue injury results in a sustained tissue inflammation in CD137−/− or CD137L−/− mice, indicating that CD137L signaling may function as an inflammation checkpoint that is required for resolution of inflammation and tissue repair. In our article recently published in Cancer Research (6), our group demonstrates that blocking of CD137L signaling either by genetic deletion of the CD137 gene or administration of anti-CD137 antibody enhances antitumor immunity to immunogenic CT26, EL-4, and Renca tumors. Mechanistic studies reveal that CD137L signaling stimulates macrophage and dendritic cell (DC) precursors to differentiate into M2 macrophages and DC2 within tumors, respectively. Thus, CD137L signaling creates a tumor microenvironment favorable for tumor growth. As Dharmadhikari and colleagues point out (8), there is a report showing an increased growth of poorly immunogenic B16F10 melanoma in CD137−/− mice (9). To our hands, there is a minimal difference in B16F10 tumor growth in wild-type versus CD137−/− mice. This discrepancy seems to be caused by ages of mice and their facility conditions. Young CD137−/− mice of 4–5 weeks of ages tend to show a hyporesponse to antigen challenge, but they become hyperresponsive as they become older (personal communications with BK Choi, National Cancer Institute of Korea). In total, I suspect that CD137L signaling should be indispensable for resolution of inflammation and that tumors should coopt CD137L signaling for their growth.Dharmadhikari and colleagues raise a question regarding the possibility of translating CD137L blockade to human cancer immunotherapy mainly based on their in vitro studies using monocytes and DCs (8). I think it is too early to try to reach any conclusion on the species difference of CD137L signaling as data have not been accumulated sufficiently to support their contention. Extracting information translatable to the human system may need a variety of experimental settings which reflect the in vivo situations. Clinical trials of anti-human CD137 mAbs may have some implications in interpreting CD137L blocking effects on anticancer therapy. Uremumab does not block the interaction of CD137 with its ligand, while utolmilumab blocks binding to endogenous CD137L (10). A small scale of clinical trials indicates that utolmilumab seems to have a superior therapeutic effect on cancer patients relative to uremumab (10). In conclusion, it is likely to take more time to obtain a consensus on the genuine function of CD137L signaling in both mice and humans.See the original Letter to the Editor, p. 1571No potential conflicts of interest were disclosed.