The HIF-1α Hypoxia Response in Tumor-Infiltrating T Lymphocytes Induces Functional CD137 (4-1BB) for Immunotherapy

Abstract

The tumor microenvironment of transplanted and spontaneous mouse tumors is profoundly deprived of oxygenation as confi rmed by positron emission tomographic (PET) imaging. CD8 and CD4 tumor-infi ltrating T lymphocytes (TIL) of transplanted colon carcinomas, melanomas, and spontaneous breast adenocarcinomas are CD137 (4-1BB)-positive, as opposed to their counterparts in tumor-draining lymph nodes and spleen. Expression of CD137 on activated T lymphocytes is markedly enhanced by hypoxia and the prolyl-hydroxylase inhibitor dimethyloxalylglycine (DMOG). Importantly, hypoxia does not upregulate CD137 in hypoxia-inducible factor (HIF)-1α-knockout T cells, and such HIF-1α-defi cient T cells remain CD137-negative even when becoming TILs, in clear contrast to co-infi ltrating and co-transferred HIF-1α-suffi cient T lymphocytes. The fact that CD137 is selectively expressed on TILs was exploited to confi ne the effects of immunotherapy with agonist anti-CD137 monoclonal antibodies to the tumor tissue. As a result, low-dose intratumoral injections avoid liver infl ammation, achieve antitumor systemic effects, and permit synergistic therapeutic effects with PD-L1/B7-H1 blockade.SIGNIFICANCE: CD137 (4-1BB) is an important molecular target to augment antitumor immunity. Hypoxia in the tumor microenvironment as sensed by the HIF-1α system increases expression of CD137 on tumor-infi ltrating lymphocytes that thereby become selectively responsive to the immunotherapeutic effects of anti-CD137 agonist monoclonal antibodies as those used in ongoing clinical trials. Cancer Discov; 2(7); 608-23.

Combining Antibody-Directed Presentation of IL-15 and 4-1BBL in a Trifunctional Fusion Protein for Cancer Immunotherapy

“…For example, it was shown in mouse models that na€ ve CD8 þ T cells can infiltrate tumors and become activated and differentiated into functional effector cells in situ (53). Studies in mice provided evidence that localized activity of IL-15 and 4-1BB in the tumor microenvironment was relevant for the respective antitumor response (54,55). Thus, in a Rag1…”

“…On the other hand, in another mouse model, it was shown that the hypoxic conditions in the tumor induced the upregulation of 4-1BB on tumorinfiltrating lymphocytes (TIL), which could be selectively activated by local, that is, intratumoral application of 4-1BB-specific monoclonal antibodies, promoting the development of an effective antitumor response without causing liver side effects. (55). Thus, local copresentation of IL-15 and 4-1BBL in the tumor microenvironment might be of especial value to support an antitumor immune response.…”

Phase Ib Study of Utomilumab (PF-05082566), a 4-1BB/CD137 Agonist, in Combination with Pembrolizumab (MK-3475) in Patients with Advanced Solid Tumors

“…Combinations of 4-1BB/CD137 agonists with PD-1 blockade may provide complementary, modulatory effects on antitumor immune responses and indeed have been shown to produce additive or synergistic antitumor activity in solid tumor models, as suggested by the PD-1 and CD137 coexpression and functional interaction demonstrated in human tumor-infiltrating lymphocytes and mouse models (11)(12)(13)(14)(15)(16)(17). The antitumor activity produced by the combination was associated with an elevated CD8 þ / regulatory T-cell ratio and increased activity of tumor-specific cytotoxic T lymphocytes in the poorly immunogenic B16F10 melanoma model.…”

Functional expression of CD137 (4-1BB) on T helper follicular cells

“…23 Hence, information on the distribution of the target in healthy and pathological tissues is crucial to understand both potential therapeutic and adverse side effects. CD137 has been reported to be expressed on tumor-infiltrating lymphocytes in both mice 24 and humans. 25 However, few data exist on expression elsewhere in human lymphoid tissues.…”