JITC Digest October 2021

JITC Editor Picks

Heterologous prime-boost vaccination targeting MAGE-type antigens promotes tumor T-cell infiltration and improves checkpoint blockade therapy

Journal for ImmunoTherapy of Cancer 2021;9:e003218 (2 September 2021)
Research

Summary:

Traditional adjuvant formulations for therapeutic cancer vaccines have preferentially induced antibody and CD4⁺ T cell responses as opposed to the cytotoxic CD8⁺ T cell response needed for tumor rejection. Using a heterologous prime-boost strategy platformed on chimpanzee adenovirus ChAdOx1 and modified vaccinia Ankara (MVA), James McAuliffe and colleagues demonstrate that therapeutic vaccination against MAGE-type antigens drives CD8⁺ T cell infiltration causing ‘cold’ tumors to become ‘hot’ and synergizes with checkpoint blockade in murine models. Low-dose weekly alternating vaccinations with ChAdOx1 and MVA vaccines carrying P1A (a murine MAGE-type antigen) led to robust polyfunctional CD8⁺ T cell infiltration in an otherwise poorly inflamed mouse tumor model. No CD4⁺ T cell responses were observed. Vaccination monotherapy early after tumor implantation slowed tumor growth and prolonged survival, but the therapeutic efficacy was diminished when administered later in the disease course. When combined with anti-PD-1, however, vaccination led to robust disease control and complete rejection in almost 50% of cases, even for established tumors. Tumor-infiltrating P1A-specific CD8⁺ T cells post-vaccination had high expression of PD-1, LAG-3 and TIM-3. Single-cell sequencing of P1A-specific CD8⁺ T cells from spleens and tumors of vaccinated animals revealed tissue-specific phenotypic distributions with enrichment for stem-like T cells residing in the spleen and effector T cells in the tumor. Vectors encoding a dual-antigen fusion of human MAGE-type antigens (MAGE-A3 and NY-ESO-1) were further shown to be immunogenic and induce interferon gamma-producing CD8⁺ T cells in outbred CD1 mice. A clinical trial is planned to investigate this prime-boost vaccine strategy in human patients.

Mitochondrial reactive oxygen species trigger metformin-dependent antitumor immunity via activation of Nrf2/mTORC1/p62 axis in tumor-infiltrating CD8T lymphocytes

Research

Summary:

Preclinical and retrospective data support enhanced anti-cancer activity of checkpoint blockade when combined with metformin, the diaguanoside medication taken regularly by more than 150 million people worldwide as standard first-line therapy for type 2 diabetes mellitus. The mechanism of metformin’s anti-tumor activity has remained elusive. Mikako Nishida et al expand on a previous observation that metformin reactivates CD8⁺ tumor-infiltrating lymphocytes (TILs) to elucidate the mechanisms underlying the immune activity of the diabetes drug, namely, a Nrf2 and mTORC1-centric feedback loop triggered by mitochondrial reactive oxygen species (ROS) that ultimately leads to a T cell-inflamed tumor microenvironment. Metformin monotherapy had anti-tumor activity in murine models, which was enhanced by anti-PD-1. Administration of the ROS scavenger MitoTEMPO eliminated the anti-tumor activity and interferon gamma secretion by CD8⁺ TILs that was induced by metformin. In vitro, metformin administration led to upregulation of Glut-1 in CD8⁺ TILs isolated from murine melanoma models when glucose was present in the culture media. No changes in Glut-1 expression were seen in CD8⁺ cells from the draining lymph node or spleen. MitoTEMPO also prevented the upregulation of Glut-1 in response to metformin in vitro. Dietary glucose supplementation further enhanced the activity of metformin and the combination treatment, but not anti-PD-1 alone. Elevated levels of Glut-1, phosphorylated S6 protein (which is downstream of mTORC1), and Ki67 were seen in CD8⁺ TILs isolated from metformin-treated mice receiving dietary glucose supplementation. Upregulation of Glut-1 in response to metformin alone, as well as in combination with anti-PD-1, was not seen in tumors with enforced defects in interferon gamma signaling or under conditions of interferon gamma blockade. Conditional deletion of Nrf2 also completely eliminated the anti-tumor effects of metformin. Ex vivo experiments using pharmacological inhibitors of mTORC1 and Nrf2 recapitulated the in vivo results.

GDF15 induces immunosuppression via CD48 on regulatory T cells in hepatocellular carcinoma

Zhaowei Wang, Lei He, Weina Li, Chuanyang Xu, Jieyu Zhang, Desheng Wang, Kefeng Dou, Ran Zhuang, Boquan Jin, Wei Zhang, Qiang Hao, Kuo Zhang, Wangqian Zhang, Shuning Wang, Yuan Gao, Jintao Gu, Lei Shang, Zhijun Tan, Haichuan Su, Yingqi Zhang, Cun Zhang, Meng Li
Journal for ImmunoTherapy of Cancer 2021;9:e002787 (6 September 2021)
Research

Summary:

Regulatory T cells (Tregs) are known to play a major immunosuppressive role in hepatocellular carcinoma (HCC). Zhaowei Wang and colleagues reveal the TGF-beta family member GDF15 as a key mediator promoting generation and functionality of Tregs in HCC. Thorough biochemical characterization directly demonstrate GDF15 acting downstream of the poorly characterized leukocyte-exclusive receptor CD48 to stabilize FOXP3 via an ERK-dependent pathway, resulting in downregulation of the E3 ubiquitin ligase STUB1. In vitro, exogenous GDF15 efficiently induced of FOXP3⁺CD25^hi Tregs with strong suppressive capacity and high expression of CTLA-4, TNFRSF4, TIGIT, and GITR. In mice, whole-body knockout GDF15 did not affect viability nor cause any obvious disease phenotypes, however, the development of orthotopic AKT- and nRasV12-driven HCC tumors was markedly decreased. Treatment with a GDF15-specific neutralizing antibody delayed HCC lesion growth, prolonged survival, and reduced Treg frequency without causing noticeable toxicity. The anti-GDF15 antibody was at least additive with anti-PD-1 and one out of eight animals treated had a curative response. An association between high GDF15 expression at the mRNA and protein level and Treg frequency was confirmed in samples from 150 human patients with HCC as well as datasets from The Cancer Genome Atlas. This study provides deep preclinical and mechanistic rationale for GDF15 as an immunotherapy target for HCC.

Simple and effective bacterial-based intratumoral cancer immunotherapy

Summary:

Intratumoral injections of pathogen-associated molecular patterns—products such as bacterial cell walls and nucleic acids that serve as danger signals for the innate immune system—have been demonstrated to induce systemic anti-tumor immune responses. To simplify the delivery of intratumoral immunotherapy and enhance anti-tumor responses, Christina S E Carroll et al took advantage of the fact that when the mineral oil, surfactant, and heat-killed Mycobacterium that constitute complete Freund’s adjuvant (CFA) are emulsified correctly, the slow kinetics of release from the injection site lead to continuous immunostimulation for multiple weeks. Injection of CFA into orthotopic murine P815 and 4T1 tumors led to statistically significant survival benefit, with six of the mice with mastocytoma completely rejecting the tumors and surviving for 2 years without recurrence. No survival benefit was seen with CFA injections into CT26 colorectal tumor models. High levels of granulocytes infiltration at days 1–5 post injection was a statistically significant correlate of survival. In a pilot veterinary trial involving 14 dogs with spontaneous tumors, complete regression was observed for three tumors after one injection of emulsified CFA, which, in 2 cases was associated with extended survival. Similar response rates with single CFA injection were also seen in horses with melanoma (regressions in n = 3 out of 11 animals). A phase I trial is ongoing at The Canberra Hospital, Australia (Australian New Zealand Clinical Trials Registry: ACTRN12616001637437), and among the first eight treated patients in the study, five showed evidence of substantial immune infiltration accompanied by extensive tumor necrosis at 4 days postinjection. No significant safety signals emerged and the injections were well tolerated. Given the wide availability of the components of CFA, tolerable safety, and minimal resources needed for administration, this single injection approach may be a promising strategy for immunotherapy in low-income countries.

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